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Animals under the sun: effects of ultraviolet radiation on mammalian skin

  • Andrzej Slominski
    Correspondence
    Address correspondence to Dr. Andrzej Slominski, Department of Pathology, Loyola University Medical Ctr, 2160 South First Ave., Maywood, IL 60153
    Affiliations
    Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA
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  • John Pawelek
    Affiliations
    Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA
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      Life on earth since inception has depended on a constant source of energy from the burning gasses of our sun. This electromagnetic energy has both life-giving and life-endangering effects, and we have learned that virtually any mechanism imaginable for adaptation to these effects seems to have a parallel in one life form or another. The sun’s energy is, of course, the ultimate source of our sustenance. In photosynthesis, organisms such as bacteria, algae, and higher plants use chlorophyll to capture energy from specific areas of the sun’s visible spectrum, allowing it to be transformed into usable chemical energy in the form of sugar, with molecular oxygen as an important side-product. Though we enjoy many beneficial effects of solar radiation, (light and warmth), humans and animals alike are also very sensitive to the harmful effects of one component of the spectrum: ultraviolet light (UVL). Chronic exposure of unprotected skin to UV results in numerous structural and biochemical changes causing premature aging. More important, UV induces mutations causing basal cell and squamous cell carcinomas, together the most prevalent cancers in the world, and deadly melanoma, whose incidence in the population is now increasing as fast or faster than any other cancer. This article describes the various hormonal and biochemical effects of UV on the skin and the corresponding responses of the skin to mount defenses, or in some cases to derive benefits from this energy. The gross effects of UV on skin—erythema, blistering, tanning, immunosuppression—are well-known; however, the number of biochemical parameters is large, revealing multiple pathways beneath these highly regulated responses.

      UVL and penetration of the skin

      UV represents electromagnetic energy covering wavelengths between 100 to 400 nm and includes vacuum UV, UVC, UVB and UVA.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
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      • et al.
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      • Goldsmith L.A.
      Vacuum UV with a wavelength of 100–200 nm is completely absorbed by air and, therefore, its biological effects cannot be measured. UVC (200–290 nm) has a profound mutagenic and lethal effect. UVC is filtered out by the upper layers of the atmosphere and is not a part of solar radiation affecting living organisms on earth;
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
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      • et al.
      therefore, its biological effect can be observed only under artificial or experimental conditions. Although UVB (290–320 nm) represents only a small fraction of solar energy reaching the earth because of partial absorption by the atmosphere, it is very efficient in inducing sunburn and pigmentation of human skin.
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      ,
      • Fitzpatrick T.B.
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      ,
      • Goldsmith L.A.
      UVA (320–400 nm) has a better penetration throughout the atmosphere but has a low efficiency in inducing erythema and melanogenesis.
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      • Fitzpatrick T.B.
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      • Wolff K.
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      ,
      • Goldsmith L.A.
      UVA is divided into UVA1 (320–340 nm) and UVA2 (340–400 nm). It has been proposed that the photobiological mechanism of UVA1 is similar to that of UVB, while UVA2 effect involves distinctive oxygen-dependent photochemistry.
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      • Peak M.J.
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      Induction of direct and indirect single-strand breaks in human cell DNA by far- and near-ultraviolet radiations Action spectrum and mechanisms.
      Because only UVA and UVB reach the surface of the earth, we will focus our discussion on the photobiologic effects of the 290–400 nm spectra of solar radiation.
      The cutaneous effects of ultraviolet radiation (UVR) are a function of the penetration and absorption of particular wavelengths. In human skin UVB is absorbed predominantly by the stratum corneum, followed by absorption in the epidermis. Although only a small fraction of the UVB reaches the dermis, its biological effect is significant.
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      • Peak M.J.
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      Induction of direct and indirect single-strand breaks in human cell DNA by far- and near-ultraviolet radiations Action spectrum and mechanisms.
      It induces immediate and delayed erythema, melanin pigmentation, solar keratosis and elastosis, and skin cancer.
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      • Carnes B.A.
      Induction of direct and indirect single-strand breaks in human cell DNA by far- and near-ultraviolet radiations Action spectrum and mechanisms.
      ,
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      Mechanisms of ultraviolet light-induced pigmentation.
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      The molecular basis of nonmelanoma cancer. New understanding.
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      Molecular basis of sun-induced premature skin ageing and retinoid antagonism.
      Transmission of UVA through epidermis of individuals with skin of low melanin content, e.g., Type I, is high, accounting for approximately 50% of energy reaching the dermis.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
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      • Wolff K.
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      ,
      • Goldsmith L.A.
      Although UVA is about 1000 times less biologically active than UVB; however, it also contributes to skin responses to solar radiation.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
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      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      UVA does not produce burning of the skin and its role in the induction of skin cancer is more limited than UVB. It appears to have a major effect on skin aging.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Peak M.J.
      • Peak J.G.
      • Carnes B.A.
      Induction of direct and indirect single-strand breaks in human cell DNA by far- and near-ultraviolet radiations Action spectrum and mechanisms.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      Other factors affecting biological responses to solar radiation include individual susceptibility, prior exposure, body site, field size, and environment.
      • Morison W.L.
      Thus, the level of skin pigmentation, genetic background, presence of photosensitizing agents, environmental temperature, humidity, and air movement influence skin responses. Similarly, prior exposure to UV will decrease the threshold response, and the skin sensitivity to solar radiation is the lowest in lower limbs, medium in upper limbs, and the highest in the trunk, neck and head.
      • Morison W.L.
      In animals the biophysical parameters of UV penetration through skin and factors affecting skin response are more varied and less defined. This is partially due to species differences and to the fact that skin of most laboratory mammals is shielded from solar radiation by fur. Therefore, studies on the biological effect of UV require generation of artificial conditions such as shaving or use of hair-deficient animals. Also the histology, physiology, and biochemistry of rodent skin differs in many aspects from its human counterpart.
      • Chase H.B.
      Growth of the hair.
      ,
      • Slominski A.
      • Paus R.
      Melanogenesis is coupled to murine anagen Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.
      These factors limit extrapolation of animal experiments to human skin. Certain areas of rodent skin such as ears, nose, tail, and paws are naturally exposed to solar radiation, and the general effects of UV such as erythema, mutagenesis, carcinogenesis, and pigmentation have been observed in both human and mammalian skin alike. Thus, despite their limitations, small laboratory animals can provide medically useful information on harmful effects of UV or, in some cases, potentially beneficial influence.
      • Studzinski G.P.
      • Moore D.
      Sunlight—can it prevent as well as cause cancer.
      For some years our laboratories and others have focused on the mechanisms of action of UV on skin, and specifically the transduction of UV energy into organized biological response(s) at both cellular and tissue levels.
      • Pawelek J.
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      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
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      Structural/functional relationship between internal and external MSH receptors Modulation of expression in Cloudman melanoma cells by UVB radiation.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      ,
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      ,
      • Slominski A.
      • Baker J.
      • Ermak G.
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      UVB stimulates production of corticotropin releasing factor (CRF) by human melanocytes.
      In this area, investigations range from cellular responses initiated by stress from UV damage, to the possibility of specific UV receptors whose activation by UV results in transduction of an electromagnetic energy signal into a defined biochemical pathway. Studies on UV-induced damage as a signaling mechanism would be analogous to cellular “SOS” mechanisms in response to oxidative, toxic, or thermal stress.
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      Mechanisms of the ultraviolet light response in mammalian cells.
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      Enhancement of DNA repair in human skin cells by thymidine dinucleotides Evidence for a p53-mediated mammalian SOS response.
      Specific transduction mechanisms require the presence of cutaneous UV receptors transducing UV energy into a second messenger system. Support for UV-induced damage as a signaling mechanism comes from the work of Gilchrest et al showing that UV-induced thymine dimers stimulate pigmentation.
      • Gilchrest B.A.
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      Mechanisms of ultraviolet light-induced pigmentation.
      Evidence has recently been provided that the eyes of both invertebrates and vertebrates, including mammals, contain specific photoreceptors for UV light.
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      Microspectrophotometric and immunocytochemical identification of ultraviolet photoreceptors in geckos.
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      Sensitivity of cones from cyprinind fish (Danio aequipinnatus) to ultraviolet and visible light.
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      The zebrafish ultraviolet cone opsin reported previously is expressed in rods.
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      Primary structure of locust opsin A speculative model which may account for ultraviolet wavelength light detection.
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      The photoreceptors and visual pigments of the garter snake (Thamnophis sirtalis) A microspectrophotometric, scanning electron microscopic and immunocytochemical study.
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      Ultraviolet plumage colors predict mate preferences in starlings.
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      Photopigments and photoentrainment in the Syrian golden hamsters.
      The precision and predictability of the cutaneous responses to UV demonstrates that little is left to chance. Like many vertebrate and invertebrate eyes, mammalian skin possesses specific mechanisms for detecting and responding to UV light. DNA damage itself appears to be one such signal, and there is evidence for other UV receptors that transduce UV signals into second messengers eliciting responses. Our laboratories have focused on the role of proopiomelanocortin (POMC) derived melanocortins and their receptors in the process of UV-induced cutaneous melanogenesis, and we will review the status of this research. Also, there are many additional pathways, which are possibly interconnected in a series of positive and negative feedback loops within and between skin cells.

      UV and melanogenesis

      In humans there is considerable evidence that melanins protect us from UV-induced skin cancers and photoaging. When mammalian skin is exposed to UV, multiple events culminate in increased melanin transfer into keratinocytes. UV causes an increase in the number of detectable melanocytes as well as an increase in their rate of melanin synthesis. UV also appears to speed up the transfer of melanin to keratinocytes. How might this signal/response system be regulated? We have proposed that melanotropins play a central role in the process and that the skin synthesizes these hormones much as they are produced in the hypothalamic/pituitary axis, through synthesis and processing of the prohormone POMC.
      • Slominski A.
      • Paus R.
      Melanogenesis is coupled to murine anagen Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      POMC derivatives such as the melanocyte stimulating hormones (MSH or melanocortins) and adrenocorticotropic hormone (ACTH) play a key role in the regulation of pigmentation throughout the vertebrates. Melanocortins belong to a class of small, structurally similar peptides ranging from 12 to 18 amino acids in length. At least 3 forms (α, β, and γ) have been identified, and a somewhat longer β form has been described in humans.
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      Human β-melanocyte-stimulating hormone revisited.
      MSH was first localized in the pituitary gland of tadpoles in 1916. It was found that removal of this gland was followed by a loss of intensity of skin color and that intensity increased again when the tadpoles were placed in a solution of pituitary extract.
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      ,
      • Atwell W.J.
      On the nature of the pigmentation changes following hypophysectomy in the frog larva.
      Decades later, melanocortin was found to be part of the larger precursor protein POMC, which is systematically cleaved by proteolytic enzymes to produce, in addition to MSH, corticotropin-like intermediate lobe peptide (CLIP), corticotropin or ACTH, lipotropin or lipotropic peptide hormone (LPH), α, β, and γ endorphins, and methionine enkephalin.
      • Inoue A.
      • Kita T.
      • Nakomura M.
      • et al.
      Nucleotide sequence of cloned cDNA for bovine corticotropin-β-lipotropin precursor.
      It has been recently found that POMC production is not limited to the pituitary gland, but also occurs in the skin and other tissues.
      • Slominski A.
      • Paus R.
      Melanogenesis is coupled to murine anagen Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.
      ,
      • Kock A.
      • Schauer E.
      • Schwarz T.
      • et al.
      MSH and ACTH production by human keratinocytes A link between the neuronal and the immune system.
      ,
      • Slominski A.
      • Paus R.
      • Mazurkiewicz J.
      Proopiomelanocortin expression in the skin during induced hair growth in mice.
      Most, if not all, of the POMC cleavage products can be assigned biological functions that involve responses to environmental stress.
      Like all hormones, MSH functions by adhering to specific receptor proteins expressed by target cells. In a mouse melanocyte, once a molecule of MSH binds to its receptor, a series of events occur that result in the stimulation of melanin-synthesizing enzymes and the production of melanin. Much of pigment cell research today is focused on understanding the molecular cascade that results from formation of the MSH-receptor complex; however, we have little information on how MSH regulates pigmentation in humans. One of the most important breakthroughs in this regard is the cloning and sequencing of the MSH receptor, a feat accomplishedby Cone and coworkers.
      • Mountjoy K.G.
      • Robins L.S.
      • Mortrud M.T.
      • et al.
      The cloning of a family of genes that encode the melanocortin receptors.
      MSH receptors are not expressed solely by melanocytes and can be found in abundance in other cells, including inflammatory mononuclear cells and keratinocytes, where their function is unknown.
      When human beings are injected with MSH, or peptides closely resembling MSH, cutaneous melanin production is accelerated at a rate similar to that seen following exposure to sunlight.
      • Lerner A.B.
      • McGuire J.S.
      Effect of alpha- and beta-melanocyte stimulating hormones on the skin color of man.
      ,
      • Levine N.
      • Sheftel S.N.
      • Eytan T.
      • et al.
      Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin.
      Interestingly, the effects of MSH are accentuated in the previously sun-exposed areas of injected volunteers.
      • Levine N.
      • Sheftel S.N.
      • Eytan T.
      • et al.
      Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin.
      Also, individuals with Addison’s disease, characterized by overproduction of ACTH (which also exhibits MSH-like activity), show generalized skin darkening that is increased in sun-exposed areas.

      Freinkel RK, Freinkel N. Cutaneous manifestation of endocrine disorders. In: Fitzpatrick TB, AZ Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine. New York: McGraw-Hill International Book Co, 1987, 2063–81.

      These observations are consistent with findings from our laboratory that one of the actions of UV on melanocytes is to increase expression of MSH receptors on the melanocyte surface, thus increasing cellular responsiveness to MSH.
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Chakraborty A.K.
      • Orlow S.J.
      • Bolognia J.L.
      • et al.
      Structural/functional relationship between internal and external MSH receptors Modulation of expression in Cloudman melanoma cells by UVB radiation.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH receptor system.
      ,
      • Chakraborty A.K.
      MSH receptors in immortalized human epidermal keratinocytes A potential mechanism for coordinate regulation of the epidermal-melanin unit.
      To our knowledge, our observations are the first to suggest a molecular mechanism for the action of UVL on the pigmentary system.
      In addition to effects on MSH receptors, UV exposure increases the levels of circulating MSH in both horses and humans.
      • Holzmann H.
      • Altmeyer P.
      • Stohr L.
      • et al.
      Die Beeinfussung des alpha-MSH durch UVA-Bestrahlunger der Haut-ein Funktionstest.
      ,
      • Holzmann H.
      • Altmeyer P.
      • Schultz-Amling W.
      Der Einfluss ultravioletter Strtahlen auf die Hypothalamus- Hypophysenachse des Menschen.
      MSH and/or POMC levels increase in mammalian skin following exposure to UVR.
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      ,
      • Kock A.
      • Schauer E.
      • Schwarz T.
      • et al.
      MSH and ACTH production by human keratinocytes A link between the neuronal and the immune system.
      Some of the above concepts are illustrated in Figure 1, Figure 2. We demonstrated, using shaved red guinea pigs, that at low, suboptimal concentrations, UVB and β-MSH (applied as a cream) act synergistically to promote melanogenesis. Shave biopsies were performed in each of the four areas shown in Figure 1. The epidermis was isolated and incubated with L-dopa to assess dopa oxidase activity. This enzyme is a key product of active differentiated melanocytes. Suboptimal MSH treatments alone had no effect on the number of active melanocytes seen in control areas of skin (control = 82 ± 27; MSH only = 56 ± 16 melanocytes/mm2). Suboptimal UVB caused a fivefold increase in active melanocytes (456 ± 79 melanocytes/mm2). However, combined suboptimal MSH/UVB treatment (2496 ± 424 melanocytes/mm2) caused a fivefold increase over the sum of active melanocytes observed with the separate treatments (512/mm2). Cell culture studies indicated that synergism occurs because UVB stimulates the production of MSH, and expression of MSH receptors, resulting in an amplified hormonal system stimulating the production and transfer of melanin.
      Figure thumbnail GR1
      Figure 1An experimental illustration of the interactions between UVB, MSH, and the mammalian pigmentary system. Shown is a red-haired guinea pig that was treated in separate areas of its shaved back for seven days with cream vehicle alone (control); suboptimal concentrations of either UVB alone or MSH alone; or MSH plus UVB. Marked pigmentation was seen with MSH and UVB in contrast to any of the treatments alone. Counts of dopa-positive melanocytes in histologic sections revealed that this was a synergistic response, i.e., UVB and MSH interacted cooperatively. Evidence from several systems suggests that the cooperativeness results from UVB causing an increase in both MSH production and MSH receptor expression as a biologic mechanism for amplifying the UVB signal/response pathways.
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Chakraborty A.K.
      • Orlow S.J.
      • Bolognia J.L.
      • et al.
      Structural/functional relationship between internal and external MSH receptors Modulation of expression in Cloudman melanoma cells by UVB radiation.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      ,
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      Other evidence shows that these processes are triggered through production of CRH and subsequent POMC production and processing, suggesting that the skin possesses a UV-responsive CRH/POMC system similar to that of the well-known hypothalamic/pituitary axis.
      Figure thumbnail GR2
      Figure 2POMC antigens in pigmented lesions of human skin. Panel a shows a dysplastic compound nevus having β-endorphin immunoreactivity. Panel b shows a control preabsorbed with β-endorphin prior to incubation of the deparafinized tissues. In panel c, ACTH immunoreactivity is seen in metastatic melanoma with the control in panel d. Certain skin lesions may be regulated by POMC-derived peptides, a notion supported in studies of melanoma cells in culture where transcription and translation of genes for POMC and receptors for the POMC-hormones, as well as stimulation of their expression by UV have been demonstrated.
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      That POMC and its derivatives can be found in human skin is demonstrated in immunohistochemical preparations in Figure 2, showing β-endorphin reactive cells from a compound dysplastic nevus (Fig 2a), and ACTH reactive cells in metastatic melanoma (Fig 2c). These experiments demonstrate that POMC-derived hormones can be found in abundance in specific cutaneous cell types. Evidence is accumulating that the skin produces these hormones following activation of its own corticotropin releasing hormone (CRH) similar to the hypothalamic/pituitary system.
      • Slominski A.
      • Baker J.
      • Ermak G.
      • et al.
      UVB stimulates production of corticotropin releasing factor (CRF) by human melanocytes.
      Other experiments demonstrated that keratinocytes and melanocytes exposed to UVB in culture show markedly enhanced production of POMC and enhanced processing to ACTH and MSH.
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Wakamatsu K.
      • Graham A.
      • Cook D.
      • et al.
      Characterisation of ACTH peptides in human skin and their activation of the melanocortin-1 receptor.

      MSH receptors expressed by human keratinocytes

      These observations provide compelling evidence of an interaction between UVL and the MSH receptor system. Such an interaction could explain how exposure to UV causes both an increase in melanogenesis and an increase in the number of active melanocytes, because MSH has been shown to regulate both pigmentation and proliferation in cultured mouse melanocytes. Melanocytes, however, do not act alone in the skin, which includes the transfer of melanin into keratinocytes resulting in increased skin melanin content.
      Since keratinocytes are the ultimate recipients of melanin, they are usually the most abundant melanin-containing cells of the skin. UVL appears to stimulate the rate of transfer of melanin from melanocytes to keratinocytes, a process that has been observed microscopically but is not understood on a biochemical level.
      • Wikswo M.A.
      Action of cyclic AMP on pigment donation between mammalian melanocytes and keratinocytes.
      ,
      • Klaus S.N.
      Pigment transfer in mammalian epidermis.
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      • Wolff K.
      Melanocyte/keratinocyte interactions in vivo The fate of melanosomes.
      The close relationship between melanocytes and keratinocytes in this intricate process suggests that there are communication mechanisms between them. Experimental results are consistent with at least four categories of UV-regulated communication: (1) Unidirectional from keratinocytes to melanocytes;
      • Kupper T.S.
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      • Flood P.
      • et al.
      Interleukin 1 gene expression in cultured human keratinocytes is augmented by ultraviolet irradiation.
      ,
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      Regulation of human melanocyte growth, dendricity, and melanization by keratinocyte derived factors.
      ,
      • Halaban R.R.
      • Langdon R.
      • Birchall N.
      • et al.
      Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes.
      (2) Unidirectional from melanocytes to keratinocytes;
      • Kock A.
      • Schauer E.
      • Schwarz T.
      • et al.
      MSH and ACTH production by human keratinocytes A link between the neuronal and the immune system.
      ,
      • Birchall N.
      • Orlow S.J.
      • Kupper T.
      • et al.
      Interactions between ultraviolet light and interleukin-1 on MSH binding in both mouse melanoma and human squamous carcinoma cells.
      ,
      • Kirnbauer R.
      • Charvat B.
      • Schauer E.
      • et al.
      Modulation of intercellular adhesion molecule-1 expression on human melanocytes and melanoma cells Evidence for a regulatory role of IL-6, IL-7, TNFβ, and UVB light.
      (3) Bidirectional between the two cell types;
      • Birchall N.
      • Orlow S.J.
      • Kupper T.
      • et al.
      Interactions between ultraviolet light and interleukin-1 on MSH binding in both mouse melanoma and human squamous carcinoma cells.
      ,
      • Kirnbauer R.
      • Charvat B.
      • Schauer E.
      • et al.
      Modulation of intercellular adhesion molecule-1 expression on human melanocytes and melanoma cells Evidence for a regulatory role of IL-6, IL-7, TNFβ, and UVB light.
      and (4) Peripheral regulation from a source other than keratinocytes and melanocytes.
      • Slominski A.
      • Paus R.
      • Mazurkiewicz J.
      Proopiomelanocortin expression in the skin during induced hair growth in mice.
      ,
      • Holzmann H.
      • Altmeyer P.
      • Stohr L.
      • et al.
      Die Beeinfussung des alpha-MSH durch UVA-Bestrahlunger der Haut-ein Funktionstest.
      ,
      • Holzmann H.
      • Altmeyer P.
      • Schultz-Amling W.
      Der Einfluss ultravioletter Strtahlen auf die Hypothalamus- Hypophysenachse des Menschen.
      ,
      • Urbanski A.
      • Schwarz T.
      • Neuner P.
      • et al.
      Ultraviolet light induces increased circulating interleukin-6 in humans.
      Such forms of communication between keratinocytes and melanocytes have not yet been demonstrated to be functional in vivo. Considering that several dozen cytokines might be involved in melanocyte/keratinocyte interactions, the question is not “whether”, but “how” the communication systems are regulated. In this regard, we began studies on keratinocytes to determine if they might express an MSH-responsive system analogous to that described in melanocytes.
      We employed cultured human squamous carcinoma cells as a model to study potential pathways of MSH action in keratinocytes.
      • Birchall N.
      • Orlow S.J.
      • Kupper T.
      • et al.
      Interactions between ultraviolet light and interleukin-1 on MSH binding in both mouse melanoma and human squamous carcinoma cells.
      We found that MSH-receptor proteins are expressed on the surface of keratinocytes and that these proteins are quite similar, to if not identical to, those expressed on mouse melanocytes.
      • Min K.
      • Pawelek J.
      Identification and characterization of β-MSH receptors on transformed human keratinocytes.
      In addition to external plasma membrane receptors for MSH, keratinocytes also expressed internal receptors, which we had previously detected in mouse melanocytes.
      • Orlow S.J.
      • Hotchkiss S.
      • Pawelek J.
      Internal binding sites for MSH in wild type and variant Cloudman melanoma cells.
      We also found that both interleukin-1 (a cytokine) and UVL had a regulatory effect on keratinocyte MSH receptors on the plasma membrane, and they had a similar effect in mouse melanocytes. Finally, we showed that the concentration of MSH-binding proteins on both melanocytes and keratinocytes is increased when the cells are exposed to MSH. MSH “up-regulates” its own receptors on both melanocytes and keratinocytes.
      We do not now know what physiological role MSH receptors might play in keratinocytes in human skin. The striking similarities between keratinocyte and melanocyte MSH receptors, both in structure and regulation by UVL interleukin-1, and MSH, suggest that keratinocyte MSH receptors may be functional in the skin’s response to UVL. It is, therefore, of great interest that the MSH-precursor POMC is synthesized in the skin and that its synthesis is stimulated by UVL.
      • Kock A.
      • Schauer E.
      • Schwarz T.
      • et al.
      MSH and ACTH production by human keratinocytes A link between the neuronal and the immune system.
      It has recently been shown that MSH can stimulate keratinocyte proliferation in mouse hair follicles.
      • Slominski A.
      • Paus R.
      • Wortsman J.
      Can some melanotropins modulate keratinocyte proliferation?.

      General responses of skin to UVR

      Besides the cutaneous pigmentary response, UV exerts pleiotropic effects on numerous skin functions (Table 1). The following sections review the molecular events surrounding some of these effects, often in the context of the pigmentary system. Several cutaneous compartments are affected, including local vascular, pigmentary, immune, and neuroendocrine systems. The consequences of their activation can be local or systemic.
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Studzinski G.P.
      • Moore D.
      Sunlight—can it prevent as well as cause cancer.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Holick M.F.
      • MacLaughlin J.A.
      • Clark M.D.
      • et al.
      Photosynthesis of previtamin D3 in human skin and the physiologic consequences.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Selgrade M.J.K.
      • Repacholi M.H.
      • Koren H.S.
      Ultraviolet radiation-induced immune modulation Potential consequences for infectious, allergic, and autoimmune disease.
      ,
      ,
      • Slominski A.
      Correspondence re GP Studzinski and DC Moore, Sunlight—can it prevent as well as cause cancer?.
      ,
      • Slominski A.
      • Mihm M.
      On a potential mechanism of skin response to stress.
      Pathologic effects of solar radiation include UV-induced carcinogenesis, aging, and photodermatoses. Although all of these mechanisms have been detailed previously, we will describe them briefly as a background for further sections and the central hypothesis of this review.
      Table 1Skin Functions Affected by UVL
      Skin CompartmentBiological Effect
      Pigmentary systemimmediate darkening, increased melanin pigmentation, production of cytokines, chemical mediators, ACTH, MSH, β-endorphin and CRH, increased melanocyte proliferation, melanoma development
      Vascular systemimmediate erythema, delayed erythema, production of chemical mediators
      Skin immune systemcytokine production, immunoinhibition, altered antigen presentation and expression of adhesion molecules, changes in immune cell composition, shift from helper to suppressor pathways
      Keratinocytesproduction of cytokines, chemical mediators, ACTH, MSH, epidermis β-endorphin and CRH, vitamin D3 production, cis-urocanic acid formation, altered keratin production and proliferation, altered expression of adhesion molecules, increased epidermal thickness, cancerogenesis
      Dermisproduction of chemical mediators, inhibition of production and stimulation of degradation of collagen and elastic fibers, changes in macromolecules composition
      The most easily measured mechanism is the vascular response to UV reflected by the development of erythema. Immediate erythema, starts shortly after the onset of UV exposure and ends within 30 minutes after the end of exposure. Delayed erythema develops after a 2–6 hour latency period, peaks at 12–16 hours, and fades after a few days.
      • Morison W.L.
      ,
      • Goldsmith L.A.
      ,
      ,
      • Gangi S.
      • Johansson O.
      Skin changes in “screen dermatitis” versus classical UV- and ionizing irradiation-related damage—similarities and differences. Two neuroscientists’ speculative review.
      The most likely mechanisms for erythema involve the production and release of mediators by damaged epidermis, e.g., prostaglandins and histamine, as well as a direct action of UV on endothelial cells.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      ,
      • Gangi S.
      • Johansson O.
      Skin changes in “screen dermatitis” versus classical UV- and ionizing irradiation-related damage—similarities and differences. Two neuroscientists’ speculative review.
      Books and reviews discuss mammalian pigmentation as well as the potential sensory functions of melanocytes.
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Slominski A.
      • Paus R.
      Melanogenesis is coupled to murine anagen Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      ,
      • Prota G.
      Pigment cell research What directions?.
      ,
      ,
      • Pawelek J.
      After dopachrome?.
      ,
      • Thody A.J.
      Epidermal melanocytes Their regulation and role in skin pigmentation.
      ,
      • Slominski A.
      • Paus R.
      • Schanderdorf D.
      Melanocytes as sensory and regulatory cells in the epidermis.
      ,
      In human skin, the pigmentary response to UV is biphasic and includes immediate skin darkening, predominantly seen with UVA, and delayed, longer lasting pigmentation that is most efficiently induced by UVB. Immediate darkening occurs within minutes in pigmented individuals and fades within one or several hours depending on the UV dose and skin type.
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      Although its mechanism is unclear, it may include melanosome movement, changes in physical properties of melanin(s), and polymerization of precursors to melanin(s). Delayed pigmentation includes de novo melanogenesis occurring within days after exposure and lasting weeks or months.
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      UVA produces dark pigmentation predominantly located in basal keratinocytes, while UVB-induced melanin is distributed throughout epidermis.
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      For unknown reasons, the most energetic and mutagenic spectrum, UVC, produces little or no pigmentation.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      Multiple explanations exist for UV-induced delayed tanning.
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      ,
      ,
      • Thody A.J.
      Epidermal melanocytes Their regulation and role in skin pigmentation.
      The tanning process can be induced by a direct UV effect on melanocytes, indirect effect mediated by induced epidermal and dermal environment, or by both. This would include effects such as oxidative stress and production of DNA photoproducts, e.g., thymidine dinucleotides,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      ,
      • Eller M.S.
      • Maeda T.
      • Magnoni C.
      • et al.
      Enhancement of DNA repair in human skin cells by thymidine dinucleotides Evidence for a p53-mediated mammalian SOS response.
      ,
      ,
      • Thody A.J.
      Epidermal melanocytes Their regulation and role in skin pigmentation.
      ,
      • Eller M.S.
      • Ostrom K.
      • Gilchrest B.
      DNA enhances melanogenesis.
      and more specific stimulation of endogenous production of chemical messengers such as arachidonic acid metabolites
      • DeLeo V.A.
      • Horlick H.
      • Hanson D.
      • et al.
      Ultraviolet radiation induces changes in membrane metabolism of human keratinocytes in culture.
      ,
      • Sondergaard J.
      • Bisgaard H.
      • Thorsen S.
      Eicosanoids in skin UV inflammation.
      or diacylglycerol,
      • Carsberg C.J.
      • Ohanian J.
      • Friedmann P.S.
      Ultraviolet radiation stimulates a biphasic pattern of 1,2-diaglycerol formation in cultured human melanocytes and keratinocytes by activation of phospholipase C and D.
      neuropeptides α-MSH and ACTH, and increased expression of their receptors.
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Chakraborty A.K.
      • Orlow S.J.
      • Bolognia J.L.
      • et al.
      Structural/functional relationship between internal and external MSH receptors Modulation of expression in Cloudman melanoma cells by UVB radiation.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      ,
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      ,
      • Schauer E.
      • Trautinger F.
      • Kock A.
      • et al.
      Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.
      ,
      • Winzen M.
      • Yaar M.
      • Burbach J.P.H.
      • et al.
      Proopiomelanocortin gene product regulation in keratinocytes.
      ,
      • Slominski A.
      • Paus R.
      • Wortsman J.
      On the potential role of proopiomelanocortin in skin physiology and pathology.
      The above factors are all known to be increased by UV exposure and they all have been shown to regulate melanogenesis in an intracrine or paracrine fashion via activation of specific biochemical pathways.
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Chakraborty A.K.
      • Orlow S.J.
      • Bolognia J.L.
      • et al.
      Structural/functional relationship between internal and external MSH receptors Modulation of expression in Cloudman melanoma cells by UVB radiation.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      ,
      • Carsberg C.J.
      • Ohanian J.
      • Friedmann P.S.
      Ultraviolet radiation stimulates a biphasic pattern of 1,2-diaglycerol formation in cultured human melanocytes and keratinocytes by activation of phospholipase C and D.
      ,
      • Schauer E.
      • Trautinger F.
      • Kock A.
      • et al.
      Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.
      ,
      • Winzen M.
      • Yaar M.
      • Burbach J.P.H.
      • et al.
      Proopiomelanocortin gene product regulation in keratinocytes.
      ,
      • Slominski A.
      • Paus R.
      • Wortsman J.
      On the potential role of proopiomelanocortin in skin physiology and pathology.
      ,
      • Im S.
      • Moro O.
      • Peng F.
      • et al.
      Activation of the cyclic AMP pathway by α-melanotropin mediates the response of human melanocytes to ultraviolet B radiation.
      Many of the above data were generated using cultured in vitro human and rodent melanocytes. Indirect effects of solar radiation on the melanocytic environment are difficult to study under such artificial culture conditions, and these would include UV-induced production of chemical, peptide, and protein mediators that activate specific receptors, or a specific transduction system in melanocytes that would stimulate melanogenesis and efficient pigment transfer to surrounding keratinocytes. Of the greatest interest are endothelins,
      • Imokawa G.
      • Yada Y.
      • Kimura M.
      Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes.
      CRH and POMC-derived MSH, and ACTH peptides, each of which cutaneous production can be stimulated by UVR.
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Chakraborty A.K.
      • Orlow S.J.
      • Bolognia J.L.
      • et al.
      Structural/functional relationship between internal and external MSH receptors Modulation of expression in Cloudman melanoma cells by UVB radiation.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      ,
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      ,
      • Slominski A.
      • Baker J.
      • Ermak G.
      • et al.
      UVB stimulates production of corticotropin releasing factor (CRF) by human melanocytes.
      ,
      • Slominski A.
      Correspondence re GP Studzinski and DC Moore, Sunlight—can it prevent as well as cause cancer?.
      ,
      • Slominski A.
      • Mihm M.
      On a potential mechanism of skin response to stress.
      ,
      • Slominski A.
      • Paus R.
      • Wortsman J.
      On the potential role of proopiomelanocortin in skin physiology and pathology.
      ,
      • Levine N.
      • Sheftel S.N.
      • Eytan T.
      • et al.
      Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin.
      An important role of the MSH signaling system in UV-induced tanning is already supported by clinical and experimental data obtained with small laboratory animals as described above.
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Bolognia J.
      • Murray M.
      • Pawelek J.
      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
      ,
      • Eller M.S.
      • Yaar M.
      • Gilchrest B.A.
      DNA damage and melanogenesis.
      UV can influence local and systemic functions of the immune system.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Gangi S.
      • Johansson O.
      Skin changes in “screen dermatitis” versus classical UV- and ionizing irradiation-related damage—similarities and differences. Two neuroscientists’ speculative review.
      ,
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      The effect can be mediated directly by absorption of energy by cells of the skin immune system, including resident and nonresident (circulating) cells, or indirectly by UV-induced activity of nonimmune cells of epidermis and dermis, including cytokines secretion and chemical mediators.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Selgrade M.J.K.
      • Repacholi M.H.
      • Koren H.S.
      Ultraviolet radiation-induced immune modulation Potential consequences for infectious, allergic, and autoimmune disease.
      ,
      ,
      • Slominski A.
      Correspondence re GP Studzinski and DC Moore, Sunlight—can it prevent as well as cause cancer?.
      ,
      • Slominski A.
      • Mihm M.
      On a potential mechanism of skin response to stress.
      ,
      • Gangi S.
      • Johansson O.
      Skin changes in “screen dermatitis” versus classical UV- and ionizing irradiation-related damage—similarities and differences. Two neuroscientists’ speculative review.
      ,
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      Following UV exposure, keratinocytes and melanocytes in the epidermis produce and secrete cytokines, such as IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, TNF-α, and GM-CSF; prostaglandins; growth factors (GF), such as basic FGF, IGF-I, TGFα; endothelins; and neuropeptides, including POMC-derived α-MSH, ACTH, and β-endorphin; and corticotropin releasing factor (CRF). The production of cytokines and mediators is also changed in nonepithelial components of epidermis and dermis, including lymphocytes, macrophages, mast cells, endothelial cells, and melanocytes. Also, trans-urocanic acid (UCA) generated in the stratum corneum after absorption of UV energy isomerizes into cis-UCA, and becomes a potent immunomodulator and immunosuppressor.
      • De Fabo E.C.
      • Noonan F.P.
      Mechanism of immune suppression by ultraviolet irradiation in vivo I. Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology.
      ,
      • Webber L.J.
      • Whang E.
      • De Fabo E.C.
      The effects of UVA-I (340–400 nm), UVA-II (320–340 nm) and UVA-I+II on the photoisomerization of urocanic acid in vivo.
      ,
      • Moodycliffe A.M.
      • Bucana C.D.
      • Kripke M.L.
      • et al.
      Differential effects of a monoclonal antibody to cis-urocanic acid on the suppression of delayed and contact hypersensitivity following ultraviolet irradiation.
      The effects on the skin’s immune system by the above-described mediators produced in reaction to UVR have been reviewed extensively.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Selgrade M.J.K.
      • Repacholi M.H.
      • Koren H.S.
      Ultraviolet radiation-induced immune modulation Potential consequences for infectious, allergic, and autoimmune disease.
      ,
      ,
      • Gangi S.
      • Johansson O.
      Skin changes in “screen dermatitis” versus classical UV- and ionizing irradiation-related damage—similarities and differences. Two neuroscientists’ speculative review.
      ,
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      ,

      Luger TA, Scholzen T, Brzoska T, et al. Cutaneous immunomodulation and coordination of skin stress responses by alpha-melanocyte-stimulating hormone. Ann NY Acad Sci 1998; in press.

      UV suppresses the activity of cutaneous antigen-presenting cells, specifically, the Langerhans’ cells’ (LC) ability to induce immunity.
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Selgrade M.J.K.
      • Repacholi M.H.
      • Koren H.S.
      Ultraviolet radiation-induced immune modulation Potential consequences for infectious, allergic, and autoimmune disease.
      ,
      ,
      • Gangi S.
      • Johansson O.
      Skin changes in “screen dermatitis” versus classical UV- and ionizing irradiation-related damage—similarities and differences. Two neuroscientists’ speculative review.
      ,
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      For example, after UV exposure there is a decrease in the number of LCs, and their morphology and composition of cell surface markers changes (including decreased expression of class II major histocompatibility molecules (MHC), intercellular adhesion molecule 1 (ICAM-1) and ATPase activity.
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Selgrade M.J.K.
      • Repacholi M.H.
      • Koren H.S.
      Ultraviolet radiation-induced immune modulation Potential consequences for infectious, allergic, and autoimmune disease.
      ,
      ,
      • Gangi S.
      • Johansson O.
      Skin changes in “screen dermatitis” versus classical UV- and ionizing irradiation-related damage—similarities and differences. Two neuroscientists’ speculative review.
      ,
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      ) Furthermore, UV stimulates influx of macrophages (CD11a-1, CD11b+), decreases viability and number of T-lymphocytes, and shifts from helper to suppressor immune pathways by decreasing the helper/suppressor T-lymphocytes ratio.
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Selgrade M.J.K.
      • Repacholi M.H.
      • Koren H.S.
      Ultraviolet radiation-induced immune modulation Potential consequences for infectious, allergic, and autoimmune disease.
      ,
      ,
      • Gangi S.
      • Johansson O.
      Skin changes in “screen dermatitis” versus classical UV- and ionizing irradiation-related damage—similarities and differences. Two neuroscientists’ speculative review.
      ,
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      Both direct and indirect actions of UV have overall immunoinhibitory effects, which may be beneficial (i.e., prevention of autoimmune reactions to new antigens exposed in the skin), or negative (i.e., compromise of the immunosurveillance of newly generated malignant cells or decrease the response against microorganisms).
      Photodermatoses are pathologic skin eruption in reaction to solar radiation,
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      including metabolic (porphyria, xeroderma pigmentosum, pellagra) idiopathic conditions (polymorphic light eruption) and disorders aggravated by solar radiation (lupus erythematosus, herpes simplex). Phototoxic reactions can be induced by topically or systemically applied compounds. In the porphyrias, porphyrin precursors of heme act as chromophores absorbing UVA energy which lead to blistering, skin fragility, pigmentation, and hirsutism on exposed areas.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      In polymorphic light eruption, a pruritic rash occurs on skin exposed to UVA (predominantly), UVB, or both (rarely) after 24–48 hours. In lupus erythematosus, a cutaneous eruption occurs most frequently on sun exposed areas, and its relapse frequently is precipitated by sunlight. Thus, UV stimulates the skin immune system to induce an immune response against its own antigens, in contrast to the previously described immunosuppressive effect of UV.
      Damaging effects of UVR include development of epithelial and melanocytic skin cancers.
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Ko C.B.
      • Walton S.
      • Keczkes K.
      • et al.
      The emerging epidemic of skin cancer.
      ,
      • Urbach F.
      Ultraviolet radiation and skin cancers in humans.
      ,
      • Nomura T.
      • Nakajima H.
      • Hongyom T.
      • et al.
      Inductions of cancer, actinic keratosis, and specific p53 mutations by UVB light in human skin maintained in severe combined immunodeficient mice.
      ,
      • Gailini M.R.
      • Leffel D.J.
      • Ziegler A.M.
      • et al.
      Relationship between sunlight exposure and a key genetic alteration in basal cell carcinoma.
      ,
      • Kusewitz D.F.
      • Applegate L.A.
      • Ley R.D.
      Ultraviolet radiation-induced skin tumors in South American opossum (Monodelphis domestica).
      ,
      • Robinson E.S.
      • VandeBerg J.L.
      • Hubbard G.B.
      • et al.
      Malignant melanoma in ultraviolet irradiated opossum Initiation in suckling young, metastasis in adults, and xenograft behavior in nude mice.
      ,
      • Ley R.D.
      Ultraviolet radiation A-induced precursors of cutaneous melanoma in Monodelphis domestica.
      ,
      • Menzies S.W.
      • Greenoak G.E.
      • Reeve V.E.
      • et al.
      Ultraviolet radiation-induced murine tumors produced in the absence of ultraviolet radiation-induced systemic tumor immunosuppression.
      ,
      • Kleint-Szanto A.J.P.
      • Silvers W.S.
      • Mintz B.
      Ultraviolet radiation-induced malignant skin melanoma in melanoma-susceptible transgenic mice.
      ,
      • Ueda M.
      • Ouhtit A.
      • Bito T.
      • et al.
      Evidence for UV-associated activation of telomerase in human skin.
      UV acts both as cancer initiator (by inducing genetic mutations) and as promoter (by generating an environment favoring proliferation and expansion of mutated cells). Skin cancer follows chronic exposure to solar radiation. There is a strong association between UVB exposure and development of squamous cell carcinomas and, to a lesser degree, basal cell carcinomas.
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Ko C.B.
      • Walton S.
      • Keczkes K.
      • et al.
      The emerging epidemic of skin cancer.
      ,
      • Urbach F.
      Ultraviolet radiation and skin cancers in humans.
      ,
      • Nomura T.
      • Nakajima H.
      • Hongyom T.
      • et al.
      Inductions of cancer, actinic keratosis, and specific p53 mutations by UVB light in human skin maintained in severe combined immunodeficient mice.
      ,
      • Gailini M.R.
      • Leffel D.J.
      • Ziegler A.M.
      • et al.
      Relationship between sunlight exposure and a key genetic alteration in basal cell carcinoma.
      ,
      • Kusewitz D.F.
      • Applegate L.A.
      • Ley R.D.
      Ultraviolet radiation-induced skin tumors in South American opossum (Monodelphis domestica).
      In epithelial cancers, UV-induced mutations in p53 and other regulatory genes such as ras play a fundamental role in carcinogenesis,
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Ko C.B.
      • Walton S.
      • Keczkes K.
      • et al.
      The emerging epidemic of skin cancer.
      ,
      • Urbach F.
      Ultraviolet radiation and skin cancers in humans.
      ,
      • Nomura T.
      • Nakajima H.
      • Hongyom T.
      • et al.
      Inductions of cancer, actinic keratosis, and specific p53 mutations by UVB light in human skin maintained in severe combined immunodeficient mice.
      ,
      • Gailini M.R.
      • Leffel D.J.
      • Ziegler A.M.
      • et al.
      Relationship between sunlight exposure and a key genetic alteration in basal cell carcinoma.
      ,
      • Kusewitz D.F.
      • Applegate L.A.
      • Ley R.D.
      Ultraviolet radiation-induced skin tumors in South American opossum (Monodelphis domestica).
      which may be amplified by the local immunosuppressive effects of solar radiation.
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      UV-associated activation of telomerase has been recently reported, suggesting another mechanism for UV-induced epidermal carcinogenesis.
      • Ueda M.
      • Ouhtit A.
      • Bito T.
      • et al.
      Evidence for UV-associated activation of telomerase in human skin.
      In the pigmentary system, UVB and UVA appear to be equally responsible for malignant transformation of melanocyte.
      • Ley R.D.
      Ultraviolet radiation A-induced precursors of cutaneous melanoma in Monodelphis domestica.
      Mutations in genes other than p53 may play an important role in melanoma development,
      • Bishop J.A.N.
      Molecular pathology of melanoma.
      in contrast to tumors of epidermal keratinocyte lineage.
      • Kang S.
      • Fisher G.J.
      • Voorhees J.J.
      Photoaging and topical tretinoin.
      In summary, there is considerable evidence that UV-induced carcinogenesis is a result of combined mutagenic and immunosuppressive effects.
      • Grossman D.
      • Leffel D.J.
      The molecular basis of nonmelanoma cancer. New understanding.
      ,
      • Kripke M.L.
      Ultraviolet radiation and immunology Something new under the sun.
      ,
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      ,
      • Ko C.B.
      • Walton S.
      • Keczkes K.
      • et al.
      The emerging epidemic of skin cancer.
      ,
      • Urbach F.
      Ultraviolet radiation and skin cancers in humans.
      ,
      • Nomura T.
      • Nakajima H.
      • Hongyom T.
      • et al.
      Inductions of cancer, actinic keratosis, and specific p53 mutations by UVB light in human skin maintained in severe combined immunodeficient mice.
      ,
      • Gailini M.R.
      • Leffel D.J.
      • Ziegler A.M.
      • et al.
      Relationship between sunlight exposure and a key genetic alteration in basal cell carcinoma.
      ,
      • Kusewitz D.F.
      • Applegate L.A.
      • Ley R.D.
      Ultraviolet radiation-induced skin tumors in South American opossum (Monodelphis domestica).
      ,
      • Robinson E.S.
      • VandeBerg J.L.
      • Hubbard G.B.
      • et al.
      Malignant melanoma in ultraviolet irradiated opossum Initiation in suckling young, metastasis in adults, and xenograft behavior in nude mice.
      ,
      • Ley R.D.
      Ultraviolet radiation A-induced precursors of cutaneous melanoma in Monodelphis domestica.
      ,
      • Menzies S.W.
      • Greenoak G.E.
      • Reeve V.E.
      • et al.
      Ultraviolet radiation-induced murine tumors produced in the absence of ultraviolet radiation-induced systemic tumor immunosuppression.
      ,
      • Kleint-Szanto A.J.P.
      • Silvers W.S.
      • Mintz B.
      Ultraviolet radiation-induced malignant skin melanoma in melanoma-susceptible transgenic mice.
      ,
      • Ueda M.
      • Ouhtit A.
      • Bito T.
      • et al.
      Evidence for UV-associated activation of telomerase in human skin.
      ,
      • Bishop J.A.N.
      Molecular pathology of melanoma.
      ,
      • Kang S.
      • Fisher G.J.
      • Voorhees J.J.
      Photoaging and topical tretinoin.
      However, some reports have suggested that moderate exposure to solar radiation may retard some forms of neoplastic processes.
      • Studzinski G.P.
      • Moore D.
      Sunlight—can it prevent as well as cause cancer.
      Chronic exposure to solar radiation stimulates the cutaneous aging process as characterized by wrinkling, dryness and roughness, loss of skin tone, and changes in melanocytic and keratinocytic functions. For example, UV causes a decrease in synthesis of collagen and elastic fibrils along with an increase in their degradation.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Fisher G.J.
      • Datta S.C.
      • Talwar H.S.
      • et al.
      Molecular basis of sun-induced premature skin ageing and retinoid antagonism.
      ,
      • Kang S.
      • Fisher G.J.
      • Voorhees J.J.
      Photoaging and topical tretinoin.
      In addition, extracellular matrix components of the dermis become altered. In the epidermis formation of freckles, solar lentigo, lentigo maligna, seborrheic keratoses and solar keratoses are accelerated.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Ko C.B.
      • Walton S.
      • Keczkes K.
      • et al.
      The emerging epidemic of skin cancer.
      ,
      • Nomura T.
      • Nakajima H.
      • Hongyom T.
      • et al.
      Inductions of cancer, actinic keratosis, and specific p53 mutations by UVB light in human skin maintained in severe combined immunodeficient mice.
      ,
      • Castanet J.
      • Ortonne J.-P.
      Pigmentary changes in aged and photoaged skin.
      Some of these processes are associated with cutaneous carcinogenesis.
      Solar radiation may also affect neuroendocrine functions of the skin, producing systemic endocrine effects. For example, the curative effect of solar radiation on rickets has been known since the 19th century.
      • Mozolowski W.
      Jedrzej Sniadecki on the cure of rickets.
      Here, UVB induces the conversion of 7-dehydroxycholesterol to provitamin D3, which in a temperature-dependent fashion isomerizes to vitamin D3.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Studzinski G.P.
      • Moore D.
      Sunlight—can it prevent as well as cause cancer.
      ,
      • Holick M.F.
      • MacLaughlin J.A.
      • Clark M.D.
      • et al.
      Photosynthesis of previtamin D3 in human skin and the physiologic consequences.
      ,
      • Tian X.Q.
      • Chen T.C.
      • Matsuoka L.Y.
      • et al.
      Kinetic and thermodynamic studies of the conversion of previtamin D3 to vitamin D3 in human skin.
      ,
      • Webb A.R.
      • Holick M.F.
      The role of sunlight in the cutaneous production of vitamin D3.
      ,
      • Walters M.R.
      Newly identified actions of the vitamin D endocrine system.
      ,
      Vitamin D3, after subsequent hydroxylation at positions 25 and 1 in the liver and kidney acts as an important hormone regulating body calcium metabolism and other organ and cellular functions.
      • Morison W.L.
      ,
      • Fitzpatrick T.B.
      • Eizen A.Z.
      • Wolff K.
      • et al.
      ,
      • Goldsmith L.A.
      ,
      • Studzinski G.P.
      • Moore D.
      Sunlight—can it prevent as well as cause cancer.
      ,
      • Holick M.F.
      • MacLaughlin J.A.
      • Clark M.D.
      • et al.
      Photosynthesis of previtamin D3 in human skin and the physiologic consequences.
      ,
      • Tian X.Q.
      • Chen T.C.
      • Matsuoka L.Y.
      • et al.
      Kinetic and thermodynamic studies of the conversion of previtamin D3 to vitamin D3 in human skin.
      ,
      • Webb A.R.
      • Holick M.F.
      The role of sunlight in the cutaneous production of vitamin D3.
      ,
      • Walters M.R.
      Newly identified actions of the vitamin D endocrine system.
      ,
      Finally, UVB stimulates production and secretion of several neuropeptides such as ACTH, MSH, β-endorphin,
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      ,
      • Slominski A.
      • Mihm M.
      On a potential mechanism of skin response to stress.
      ,
      • Schauer E.
      • Trautinger F.
      • Kock A.
      • et al.
      Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.
      ,
      • Winzen M.
      • Yaar M.
      • Burbach J.P.H.
      • et al.
      Proopiomelanocortin gene product regulation in keratinocytes.
      ,
      • Slominski A.
      • Paus R.
      • Wortsman J.
      On the potential role of proopiomelanocortin in skin physiology and pathology.
      ,

      Luger TA, Scholzen T, Brzoska T, et al. Cutaneous immunomodulation and coordination of skin stress responses by alpha-melanocyte-stimulating hormone. Ann NY Acad Sci 1998; in press.

      ,
      • Ghanem G.
      • Verstegen J.
      • DeRijcke
      • et al.
      Studies of factors influencing human plasma α-MSH.
      and CRH.
      • Slominski A.
      • Baker J.
      • Ermak G.
      • et al.
      UVB stimulates production of corticotropin releasing factor (CRF) by human melanocytes.
      ,
      • Slominski A.
      • Mihm M.
      On a potential mechanism of skin response to stress.
      Thus, UV may stimulate some neuroendocrine functions of skin through generation of vitamin D3 or production of CRH, MSH, ACTH and β-endorphin neuropeptides.

      Transduction of solar radiation into organized biological responses

      Because skin is the major recipient of UVR radiation, mechanisms may have developed during evolution for transformation of solar radiant energy into organized biological responses. Such mechanisms would include activation of pathways buffering or counteracting the damaging effects of UV.
      UV-induced cellular damage includes production of reactive oxygen species and free radicals, protein damage, and direct DNA damage. Oxidative stress and protein damage lead to membrane disruption, multimerization and clustering of cell surface receptors, activation of tyrosine kinases and phospholipases, release of arachidonic acid and hydrolysis of inositol phospholipids.
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Mai S.
      • Stein B.
      • Van Den Berg S.
      • et al.
      Mechanisms of the ultraviolet light response in mammalian cells.
      ,
      • Carsberg C.J.
      • Ohanian J.
      • Friedmann P.S.
      Ultraviolet radiation stimulates a biphasic pattern of 1,2-diaglycerol formation in cultured human melanocytes and keratinocytes by activation of phospholipase C and D.
      ,
      • Rosette C.
      • Karin M.
      Ultraviolet light and osmostic stress Activation of the JNK cascade through multiple growth factor and cytokine receptors.
      ,
      • Devary Y.
      • Rosetter C.
      • DiDonato J.A.
      • et al.
      NF-kB activation by ultraviolet light not dependent on a nuclear signal.
      ,
      • Basu-Modal S.
      • Tyrrell R.M.
      Singlet oxygen A primary effector in the ultravioletA/near-visible light induction of the human heme oxygenase gene.
      ,
      • Devary Y.
      • Gottlieb R.A.
      • Smeal T.
      • et al.
      The mammalian ultraviolet response is triggered by activation of src tyrosine kinases.
      DNA damage may induce production of nuclear signals activating the genome directly, or indirectly via membrane-associated signaling processes.
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Mai S.
      • Stein B.
      • Van Den Berg S.
      • et al.
      Mechanisms of the ultraviolet light response in mammalian cells.
      ,
      • Maytin E.V.
      Heat shock proteins and molecular chaperones Implications for adaptive responses in the skin.
      ,
      • Eller M.S.
      • Maeda T.
      • Magnoni C.
      • et al.
      Enhancement of DNA repair in human skin cells by thymidine dinucleotides Evidence for a p53-mediated mammalian SOS response.
      ,
      • Warmuth Harth Y.
      • Matsui M.S.
      • et al.
      Ultraviolet radiation induces phosphorylation of the epidermal growth factor receptor.
      ,
      • Conconi A.
      • Smerdon M.J.
      • Howe G.A.
      • et al.
      The octadecanoid signalling pathway in plants mediates a response to ultraviolet radiation.
      ,
      • Price M.A.
      • Cruzalegui F.H.
      • Treisman R.
      The p38 and ERKMAP kinase pathways cooperate to activate ternary complex factors and c-fos transcription in response to UV light.
      ,
      • Liu Z.-G.
      • Baskaran R.
      • Lea-Chou E.T.
      • et al.
      Three distinct signalling responses by murine fibroblasts to genotoxic stress.
      ,
      • Ortin V.R.
      • McLenigan M.
      • Takao M.
      • et al.
      Translocation of a UV-damaged binding protein into a tight association with chromatin after treatment of mammalian cells with UV light.
      ,
      • Ronai Z.
      • Rutberg S.
      • Yang Y.M.
      UV-responsive element (TGACAACA) from rat fibroblasts to human melanomas.
      These induced metabolic events constitute rescue pathways from lethal or sublethal insults. On the organ level, rescue pathway-generated signal molecules activate regulatory cytokine/neuropeptide networks that induce phenotypic changes buffering or counteracting cellular or tissue damage.
      Melanin pigmentation is one well-known response to UV action and is an example of UV-activated signal transduction followed by a biologic effect. In the pigmentary system potential chemical (“second”) messengers of UV include nitric oxide (NO), cGMP, diaglycerol (DAG), inositol triphosphate (IP3), arachidonic acid metabolites, thymidine dimers
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Eller M.S.
      • Maeda T.
      • Magnoni C.
      • et al.
      Enhancement of DNA repair in human skin cells by thymidine dinucleotides Evidence for a p53-mediated mammalian SOS response.
      ,
      • Eller M.S.
      • Ostrom K.
      • Gilchrest B.
      DNA enhances melanogenesis.
      ,
      • Carsberg C.J.
      • Ohanian J.
      • Friedmann P.S.
      Ultraviolet radiation stimulates a biphasic pattern of 1,2-diaglycerol formation in cultured human melanocytes and keratinocytes by activation of phospholipase C and D.
      ,
      • Eller M.S.
      • Yaar M.
      • Gilchrest B.A.
      DNA damage and melanogenesis.
      ,
      • Hanson D.L.
      • DeLeo V.A.
      Longwave ultraviolet radiation stimulates arachidonic acid release and cyclooxygenase activity in mammalian cells in culture.
      ,
      • DeLeo V.
      • Schleide S.
      • Meshulam J.
      • et al.
      Ultraviolet radiation alters choline phospholipid metabolism in human keratinocytes.
      ,
      • Romero-Graillet C.
      • Aberdam E.
      • Biagoli N.
      • et al.
      Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes.
      ,
      • Romero-Graillet C.
      • Aberdam E.
      • Clement M.
      • et al.
      Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis.
      and intermediates of melanogenesis such as L-DOPA, 5,6-dihydroxyindole (DHI), DHI-2-carboxylic acid (DHICA), and 5-S-cysteinyl DOPA (CD).
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Prota G.
      Pigment cell research What directions?.
      ,
      • Slominski A.
      • Paus R.
      • Schanderdorf D.
      Melanocytes as sensory and regulatory cells in the epidermis.
      ,
      • Pawelek J.
      • Bolognia J.
      • McLane J.
      • et al.
      A possible role of melanin precursors in regulating both pigmentation and proliferation of melanocytes.
      ,
      • Slominski A.
      • Paus R.
      Are L-tyrosine and L-dopa hormone-like bioregulators.
      ,
      • Slominski A.
      • Paus R.
      Towards defining receptors for L-tyrosine and L-DOPA.
      ,
      • Memoli S.
      • Napolitano A.
      • d’Ischia M.
      • et al.
      Diffusible melanin-related metabolites are potent inhibitors of lipid peroxidation.
      These molecules, synthesized after UVR, can stimulate melanogenesis and regulate functions of other cells. The mechanism of action of some of these compounds has been investigated extensively.
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
      • Prota G.
      Pigment cell research What directions?.
      ,
      • Carsberg C.J.
      • Ohanian J.
      • Friedmann P.S.
      Ultraviolet radiation stimulates a biphasic pattern of 1,2-diaglycerol formation in cultured human melanocytes and keratinocytes by activation of phospholipase C and D.
      ,
      • Romero-Graillet C.
      • Aberdam E.
      • Biagoli N.
      • et al.
      Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes.
      For example, stimulation of pigmentation by DAG may involve activation of protein kinase C (PKC).
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Carsberg C.J.
      • Ohanian J.
      • Friedmann P.S.
      Ultraviolet radiation stimulates a biphasic pattern of 1,2-diaglycerol formation in cultured human melanocytes and keratinocytes by activation of phospholipase C and D.
      UV can also directly activate PKC.
      • Matsui M.S.
      • DeLeo V.
      Induction of protein kinase C activity by ultraviolet radiation.
      Thymidine dimers can directly activate tyrosinase gene and upregulates the MSH-MSH receptor signaling system,
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.
      ,
      • Eller M.S.
      • Ostrom K.
      • Gilchrest B.
      DNA enhances melanogenesis.
      supporting previous findings that regulated signal transduction through MSH receptors and activation of cAMP dependent pathways play a crucial role in UV-regulated melanocyte activity.
      • Pawelek J.
      • Chakraborty A.K.
      • Osber M.P.
      • et al.
      Molecular cascade in UV-induced melanogenesis A central role for melanotropins?.
      ,
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      Structural/functional relationship between internal and external MSH receptors Modulation of expression in Cloudman melanoma cells by UVB radiation.
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      • Bolognia J.
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      UVB-induced melanogenesis may be mediated through the MSH-receptor system.
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      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
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      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      ,
      • Im S.
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      Activation of the cyclic AMP pathway by α-melanotropin mediates the response of human melanocytes to ultraviolet B radiation.
      Gilchrest et al. have shown that thymidine dimer induces a second photoprotective response, enhanced repair of DNA by upregulation of ERCC3 and GADD45 and by cell cycle inhibition mediated by SDII.
      • Eller M.S.
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      Enhancement of DNA repair in human skin cells by thymidine dinucleotides Evidence for a p53-mediated mammalian SOS response.
      This system is enhanced by a thymidine dimer-activated p53 protein.
      • Eller M.S.
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      Enhancement of DNA repair in human skin cells by thymidine dinucleotides Evidence for a p53-mediated mammalian SOS response.
      NO stimulates both cGMP production and melanogenesis, which is prevented by inhibitors of guanylate cyclase and cGMP-dependent kinases.
      • Romero-Graillet C.
      • Aberdam E.
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      Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes.
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      • Romero-Graillet C.
      • Aberdam E.
      • Clement M.
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      Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis.
      On the other hand, induction of melanogenesis stimulates production of potential second messengers such as L-DOPA, DHI, DHICA, and CD that can regulate melanocytes and other cell functions.
      • Slominski A.
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      Melanocytes as sensory and regulatory cells in the epidermis.
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      A possible role of melanin precursors in regulating both pigmentation and proliferation of melanocytes.
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      Are L-tyrosine and L-dopa hormone-like bioregulators.
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      • Slominski A.
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      Towards defining receptors for L-tyrosine and L-DOPA.
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      • Memoli S.
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      Diffusible melanin-related metabolites are potent inhibitors of lipid peroxidation.
      In addition, UV by induction of phospholipase A2 stimulates release of arachidonic acid metabolites
      • Hanson D.L.
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      Longwave ultraviolet radiation stimulates arachidonic acid release and cyclooxygenase activity in mammalian cells in culture.
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      • DeLeo V.
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      Ultraviolet radiation alters choline phospholipid metabolism in human keratinocytes.
      which regulate melanocyte activity.
      • Gilchrest B.A.
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      Mechanisms of ultraviolet light-induced pigmentation.
      Chemical messengers of UVR that are involved in induction of melanogenesis (NO, DAG, thymidine dimers) and erythema (arachidonic acid metabolites, NO) have been identified but the mechanism of their production is under intensive study. UV can directly induce of DNA damage and/or repair process generating promelanogenic thymidine dimer messengers.
      • Eller M.S.
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      • Magnoni C.
      • et al.
      Enhancement of DNA repair in human skin cells by thymidine dinucleotides Evidence for a p53-mediated mammalian SOS response.
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      • Eller M.S.
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      DNA enhances melanogenesis.
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      • Eller M.S.
      • Yaar M.
      • Gilchrest B.A.
      DNA damage and melanogenesis.
      UV also acts at the level of the cell membrane by induction of DAG release, activating phosphatidylinositol (PI) specific phospholipase C which generates IP3 and DAG, and activation of phosphatidylcholine (PC) specific phospholipase D leading to production of DAG.
      • Carsberg C.J.
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      • Friedmann P.S.
      Ultraviolet radiation stimulates a biphasic pattern of 1,2-diaglycerol formation in cultured human melanocytes and keratinocytes by activation of phospholipase C and D.
      UV induces a constitutive form of NO synthase and NO stimulates cGMP production.
      • Romero-Graillet C.
      • Aberdam E.
      • Biagoli N.
      • et al.
      Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes.
      ,
      • Romero-Graillet C.
      • Aberdam E.
      • Clement M.
      • et al.
      Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis.
      It is unclear which mechanism generating messengers is activated directly by UV or is initiated through oxidative damage and production of free radicals.
      Analagous to the stress response in single cells in vitro, skin may contain an organ equivalent for its own responses to oxidative, chemical or thermal stress,
      • Mai S.
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      Mechanisms of the ultraviolet light response in mammalian cells.
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      • Maytin E.V.
      Heat shock proteins and molecular chaperones Implications for adaptive responses in the skin.
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      • Eller M.S.
      • Maeda T.
      • Magnoni C.
      • et al.
      Enhancement of DNA repair in human skin cells by thymidine dinucleotides Evidence for a p53-mediated mammalian SOS response.
      ,
      • Conconi A.
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      • Howe G.A.
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      The octadecanoid signalling pathway in plants mediates a response to ultraviolet radiation.
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      • Liu Z.-G.
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      Three distinct signalling responses by murine fibroblasts to genotoxic stress.
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      • Ronai Z.
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      • Yang Y.M.
      UV-responsive element (TGACAACA) from rat fibroblasts to human melanomas.
      triggered, for example, by hormone-receptor cascade mechanisms, such as the endothelin/endothelin receptor system.
      • Imokawa G.
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      • Kimura M.
      Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes.
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      • Tsuboi R.
      • Sato C.
      • Oshita Y.
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      Ultraviolet B irradiation increases endothelin-1 and endothelin receptor expression in culture human keratinocytes.
      A second organ equivalent already recognized as a main coordinator of systemic stress responses is a local equivalent of the hypothalamic-pituitary axis,
      • Slominski A.
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      On a potential mechanism of skin response to stress.
      ,
      • Slominski A.
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      • Wortsman J.
      On the potential role of proopiomelanocortin in skin physiology and pathology.
      composed of skin-derived CRH, POMC products (ACTH, MSH, β-endorphin and corresponding receptors). Production and secretion of CRH and POMC peptides by cutaneous cells is stimulated by UV.
      • Chakraborty A.
      • Slominski A.
      • Ermak G.
      • et al.
      Ultraviolet and melanocyte-stimulating hormone (MSH) stimulate mRNA production of αMSH receptors and proopiomelanocortin-derived peptides in mouse melanoma cells and transformed keratinocytes.
      ,
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      ,
      • Slominski A.
      • Baker J.
      • Ermak G.
      • et al.
      UVB stimulates production of corticotropin releasing factor (CRF) by human melanocytes.
      ,
      • Schauer E.
      • Trautinger F.
      • Kock A.
      • et al.
      Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.
      ,
      • Winzen M.
      • Yaar M.
      • Burbach J.P.H.
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      Proopiomelanocortin gene product regulation in keratinocytes.
      By analogy with pituitary, function peptide production might be predicted to be under positive control of cAMP, Ca++, and PKC-activated pathways.
      ,
      • Vamvakopoulos N.C.
      • Chrousos G.P.
      Hormonal regulation of human corticotropin-releasing hormone gene expression Implications for the stress response and immune/inflammatory reaction.
      ,
      • Koch B.
      • Lutz-Bucher B.
      Inhibition of protein kinase C activity in cultured pituitary cells attenuates both cyclic AMP-independent and -dependent secretion of ACTH.
      ,
      • Turnbull A.V.
      • River C.
      Corticotropin-releasing factor, vasopressin, and prostaglandins mediate, and nitric oxide restrains, the hypothalamic-pituitary-adrenal response to acute local inflammation in the rat.
      ,
      • Nye E.J.
      • Hockings G.I.
      • Grice J.E.
      • et al.
      Aspirin inhibits vasopressin-induced hypothalamic-pituitary-adrenal activity in normal humans.
      ,
      • Grossman A.
      • Costa A.
      • Forsling M.L.
      • et al.
      Gaseous neurotransmitters in the hypothalamus. The role of nitric oxide and carbon monoxide in neuroendocrinology.
      In addition, arachidonic acid metabolites can stimulate CRH-POMC axis, while NO is inhibitory.
      • Turnbull A.V.
      • River C.
      Corticotropin-releasing factor, vasopressin, and prostaglandins mediate, and nitric oxide restrains, the hypothalamic-pituitary-adrenal response to acute local inflammation in the rat.
      ,
      • Nye E.J.
      • Hockings G.I.
      • Grice J.E.
      • et al.
      Aspirin inhibits vasopressin-induced hypothalamic-pituitary-adrenal activity in normal humans.
      ,
      • Grossman A.
      • Costa A.
      • Forsling M.L.
      • et al.
      Gaseous neurotransmitters in the hypothalamus. The role of nitric oxide and carbon monoxide in neuroendocrinology.
      In mammalian skin the effect of NO may not necessarily be inhibitory because it can increase intracellular levels of cAMP,
      • Romero-Graillet C.
      • Aberdam E.
      • Biagoli N.
      • et al.
      Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes.
      and stimulate CRH production.
      • Grossman A.
      • Costa A.
      • Forsling M.L.
      • et al.
      Gaseous neurotransmitters in the hypothalamus. The role of nitric oxide and carbon monoxide in neuroendocrinology.
      Preliminary support for a role of cAMP in cutaneous POMC peptide production has been provided.
      • Chakraborty A.
      • Funasaka Y.
      • Slominski A.
      • et al.
      Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture Regulation by UVB.
      Another element of the CRH-POMC network is a mechanism explaining receptor and signal transduction. Part of the skin pigmentary response is regulated at the MSH receptor level, with stimulation of MSH receptor expression and an increased phenotypic responsiveness of target cells to exogenous MSH.
      • Gilchrest B.A.
      • Park H.-Y.
      • Eller M.S.
      • et al.
      Mechanisms of ultraviolet light-induced pigmentation.