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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.
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;
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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;
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.
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.
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.
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
immediate darkening, increased melanin pigmentation, production of cytokines, chemical mediators, ACTH, MSH, β-endorphin and CRH, increased melanocyte proliferation, melanoma development
immediate erythema, delayed erythema, production of chemical mediators
Skin immune system
cytokine production, immunoinhibition, altered antigen presentation and expression of adhesion molecules, changes in immune cell composition, shift from helper to suppressor pathways
production 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
production 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.
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.
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.
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,
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.
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,
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.
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.
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.
) 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.
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,
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.
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.
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.
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.
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.
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.
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.
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
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.
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.