Ultraviolet Radiation-induced Immunosuppression Research Articles

Ultraviolet radiation-induced immunosuppression and its relevance for skin carcinogenesis.

The realisation that UV radiation (UVR) exposure could induce a suppressed immune environment for the initiation of carcinogenesis in the skin was first described more than 40 years ago. Van der Leun and his colleagues contributed to this area in the 1980s and 90s by experiments in mice involving UV wavelength and dose-dependency in the formation of such tumours, in addition to illustrating both the local and systemic effect of the UVR on the immune system. Since these early days, many aspects of the complex pathways of UV-induced immunosuppression have been studied and are outlined in this review. Although most experimental work has involved mice, it is clear that UVR also causes reduced immune responses in humans. Evidence showing the importance of the immune system in determining the risk of human skin cancers is explained, and details of how UVR exposure can down-regulate immunity in the formation and progression of such tumours reviewed. With increasing knowledge of these links and the mechanisms of UVR-induced immunosuppression, novel approaches to enhance immunity to skin tumour antigens in humans are becoming apparent which, hopefully, will reduce the burden of UVR-induced skin cancers in the future.

Editor's Note: Prevention of Ultraviolet Radiation-Induced Immunosuppression by (-)-Epigallocatechin-3-Gallate in Mice Is Mediated through Interleukin 12-Dependent DNA Repair.

Purpose: Solar UV radiation–induced immunosuppression is considered to be a risk factor for melanoma and nonmelanoma skin cancers. We previously have shown that topical application of (−)-epigallocatechin-3-gallate (EGCG) prevents UV-induced immunosuppression in mice. We studied whether prevention of UV-induced immunosuppression by EGCG is mediated through interleukin 12 (IL-12)–dependent DNA repair. Experimental Design: IL-12 knockout (KO) mice on C3H/HeN background and DNA repair–deficient cells from xeroderma pigmentosum complementation group A ( XPA ) patients were used in this study. The effect of EGCG was determined on UV-induced suppression of contact hypersensitivity and UV-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPD) in mice and XPA -deficient cells using immunohistochemistry and dot-blot analysis. Results: Topical treatment with EGCG prevented UV-induced suppression of the contact hypersensitivity in wild-type (WT) mice but did not prevent it in IL-12 KO mice. Injection of anti-IL-12 monoclonal antibody to WT mice blocked the preventive effect of EGCG on UV-induced immunosuppression. EGCG reduced or repaired UV-induced DNA damage in skin faster in WT mice as shown by reduced number of CPDs + cells and reduced the migration of CPD + antigen-presenting cells from the skin to draining lymph nodes. In contrast, this effect of EGCG was not seen in IL-12 KO mice. Further, EGCG was able to repair UV-induced CPDs in XPA -proficient cells obtained from healthy person but did not repair in XPA -deficient cells, indicating that nucleotide excision repair mechanism is involved in DNA repair. Conclusions: These data identify a new mechanism by which EGCG prevents UV-induced immunosuppression, and this may contribute to the chemopreventive activity of EGCG in prevention of photocarcinogenesis.

Honokiol inhibits ultraviolet radiation-induced immunosuppression through inhibition of ultraviolet-induced inflammation and DNA hypermethylation in mouse skin

Ultraviolet (UV) radiation exposure induces immunosuppression, which contributes to the development of cutaneous malignancies. We investigated the effects of honokiol, a phytochemical found in plants of the genus Magnolia, on UVB-induced immunosuppression using contact hypersensitivity (CHS) as a model in C3H/HeN mice. Topical application of honokiol (0.5 and 1.0 mg/cm2 skin area) had a significant preventive effect on UVB-induced suppression of the CHS response. The inflammatory mediators, COX-2 and PGE2, played a key role in this effect, as indicated by honokiol inhibition of cyclooxygenase-2 (COX-2) expression and PGE2 production in the UVB-exposed skin. Honokiol application also inhibited UVB-induced DNA hypermethylation and its elevation of the levels of TET enzyme, which is responsible for DNA demethylation in UVB-exposed skin. This was consistent with the restoration of the CHS response in mice treated with the DNA demethylating agent, 5-aza-2′-deoxycytidine, after UVB exposure. There was no significant difference in the levels of inhibition of UVB-induced immunosuppression amongst mice that were treated topically with available anti-cancer drugs (imiquimod and 5-fluorouracil). This study is the first to show that honokiol has the ability to inhibit UVB-induced immunosuppression in preclinical model and, thus, has potential for use as a chemopreventive strategy for UVB radiation-induced malignancies.

Ultraviolet Radiation-Induced Immunosuppression: Induction of Regulatory T Cells.

Solar/ultraviolet (UV) radiation exerts a variety of biological effects, including suppression of the immune system. UV-induced immunosuppression is induced by suberythemogenic/physiological UV doses, and it affects primarily T-cell driven immune reactions. Another characteristic feature of UV-induced immunosuppression is its antigen-specificity. This is due to the induction of T cells with suppressive features, called regulatory T cells. Since UV-induced regulatory T cells may harbor therapeutic potential phenotypic and functional characterization of these cells is ongoing. Most of these studies have been performed in the murine model of contact hypersensitivity. In this protocol we describe a method for the UV-induced suppression of the induction of contact hypersensitivity and the adoptive transfer of immune response.

Prevention of ultraviolet radiation‑induced immunosuppression by sunscreen in Candidaalbicans‑induced delayed‑type hypersensitivity.

Ultraviolet (UV) radiation-induced immunosuppression leading to skin cancer has received increased attention in previous years. The present study aimed to investigate the immunoprotection offered by Anthelios sunscreen in a mouse model of Candida albicans-induced delayed-type hypersensitivity. Anthelios sunscreen was applied to the skin on the dorsal skin of BALB/c mice treated with a sub-erythema dose of solar-simulated radiation. Delayed-type hypersensitivity was induced by immunization with Candida albicans. Changes in the skin thickness of the foot pads were measured, and immunosuppression rates were also evaluated. The expression levels of CD207, CD80 and CD86 in the Langerhans cells were semi-quantitatively detected using Western blotting and immunohistochemical assays. The delayed-type hypersensitivity mouse model was successfully established. The minimal erythema doses of UVA and UVB exposure to the mice were 2,000 and 145 mJ/cm2, respectively. The immunosuppression rates in the sunscreen group and non-sunscreen group were 24.39 and 65.85%, respectively (P<0.01). The results of the Western blotting and immunohistochemistry showed that the expression levels of CD207 (P<0.01), CD80 (P<0.05) and CD86 (P<0.01) were higher in the sunscreen group, compared with those in the non-sunscreen group. UV exposure reduced Candida albicans antigen-induced delayed-type hypersensitivity. Anthelios sunscreen was found to protect the skin from immunosuppression through the activation of epidermal Langerhans cells.

An action spectrum for ultraviolet radiation-induced immunosuppression in humans

The immune-suppressive effects of sunlight play a central role in skin carcinogenesis. Ultraviolet (UV) B radiation is highly immunosuppressive even at suberythemal doses, and longwave UVA is now also recognized to cause immunosuppression in humans. The relative contributions of UVA and UVB to immunosuppression by incidental daily sun exposure are, however, unclear. We previously determined wavelength dependencies for immunosuppression by UVB and UVA wavebands in humans. We now aimed to calculate relative and solar immune-suppressive effectiveness across the UVB and UVA spectra. We used the nickel model of recall contact hypersensitivity to determine UV immunosuppression dose responses and minimum immune suppression doses (MISDs) at 11 narrowbands from 289 to 392 nm. The relative immune-suppressive effectiveness of each narrowband was then determined as 1/MISD vs. wavelength. This curve was multiplied by the solar spectrum to show the relative immune-suppressive effectiveness of each waveband in sunlight. We found peaks of immune-suppressive effectiveness in the UVB waveband at 300 nm and in the UVA at 370 nm. Because of the far greater amount of longwave UVA in sunlight, the relative solar immune-suppressive effectiveness of UVA was threefold higher than that of UVB at doses equivalent to sun exposure from normal daily activities. Longwave UVA, which abuts the visible light spectrum and is less effectively filtered by sunscreens than UVB, is likely to be the largest contributor to immunosuppression resulting from incidental daily sun exposure.

Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans

Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans

Molecular mechanisms of ultraviolet radiation-induced immunosuppression

Solar ultraviolet radiation (UVR) is well known for its immunosuppressive properties. UVR can suppress immune reactions both in a local and a systemic fashion. One of the major molecular mediators of photoimmunosuppression is UVR-induced DNA damage. In contrast to immunosuppressive drugs, UVR does not act in a general but antigen-specific fashion. This is due to the induction of regulatory T cells. Epidermal Langerhans cells harboring UVR-induced DNA damage appear to be essentially involved in the induction of these cells. Cytokines including interleukin (IL)-12, -18 and -23 exert the capacity to reduce UVR-induced DNA damage via induction of DNA repair. Accordingly, these cytokines prevent UVR-mediated immunosuppression. In contrast to IL-18, IL-12 and IL-23 can also inhibit the suppressive activity of regulatory T cells by a mechanism which still needs to be determined. Clarification of the molecular mechanisms underlying UVR-induced immunosuppression will help to develop new immunosuppressive therapeutic strategies by utilizing UVR-induced regulatory T cells for the treatment of immune-mediated diseases. In addition, these insights will contribute to a better understanding of photocarcinogenesis since suppression of the immune system by UVR essentially contributes to the induction of skin cancer.

Langerhans cells: critical regulators of skin immunity?

Langerhans cells (LC) are members of the heterogenous family of professional antigen presenting dendritic cells (DC). They are identified by the C-type lectin receptor Langerin and form a contiguous network in the epidermis. Consequently, LC are an integral part of the skin barrier to the environment and were considered to be critical inducers of skin immunity, whereas dermal DC were largely overlooked. However, with the identification of a distinct subset of Langerin expressing dermal DC, the situation in the skin has become more complex and the relative contribution of the different cutaneous DC populations in balancing immunity and tolerance has become a matter of active debate. Here, we briefly review the classical paradigm and recent challenges of LC function, before focusing on advances concerning their role in contact hypersensitivity and ultraviolet radiation-induced immunosuppression obtained with in vivo LC ablation models. We then discuss novel LC/DC-specific gene targeting approaches currently used to dissect the role of the regulatory cytokines transforming growth factor-beta and interleukin-10 to govern LC and DC function in vivo. This second generation of LC-specific genetically engineered mice will considerably extend our understanding of the molecular control of LC function in regulating skin immunity and tolerance in the near future.

Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans

Ultraviolet (UV) radiation can profoundly suppress the cutaneous immune system, thus enhancing carcinogenesis. Agents that prevent UV-induced immunosuppression may thus reduce skin cancer. Nicotinamide (vitamin B3) prevents UV-induced immunosuppression and carcinogenesis in mice, and solar-simulated (ss) UV-induced immunosuppression in humans. Its effectiveness against different UV wavebands and mechanism of action is as yet unknown. To determine the effects and mechanisms of topical nicotinamide on UV-induced suppression of delayed type hypersensitivity (DTH) responses in humans. Healthy Mantoux-positive volunteers in four randomised, double-blinded studies were irradiated with solar-simulated (ss)UV (UVB + UVA) or narrowband UVB (300 nm) or UVA (385 nm). Topical nicotinamide (0.2% or 5%) or its vehicle were applied immediately after each irradiation. Mantoux testing was performed at irradiated sites and adjacent unirradiated control sites 48 h after the first irradiation and measured 72 h later. Immunosuppression was calculated as the difference in Mantoux-induced erythema and induration at test sites compared to control sites. Human keratinocyte cell cultures, with and without ssUV and nicotinamide, were used for quantitative real-time reverse transcriptase-polymerase chain reaction assessment of TP53 and enzymes that regulate oxidative phosphorylation. Nicotinamide cooperated with ssUV to increase enzymes involved in cellular energy metabolism and p53, and significantly protected against immunosuppression caused by UVB, longwave UVA and single and repeated ssUV exposures. Longwave UVA, which is poorly filtered by most sunscreens, was highly immune suppressive even at doses equivalent to 20 min of sun exposure. Nicotinamide, which protected against both UVB and UVA, is a promising agent for skin cancer prevention.

Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans

Cutaneous immunity, which is a key defence against the development of skin cancers, is suppressed by even small doses of ultraviolet (UV) radiation. Preventing this UV-induced immunosuppression may therefore reduce the incidence of skin cancer. Nicotinamide (vitamin B3) has immune-protective and cancer-preventive effects against UV radiation in mice, and we have shown previously that topical nicotinamide is immune protective in humans. Using the Mantoux model of skin immunity in healthy volunteers, we compared oral nicotinamide to placebo (both administered for 1 week) in a randomized, double-blinded, crossover design against the effects of solar-simulated ultraviolet (ssUV) radiation on delayed-type hypersensitivity to tuberculin purified protein derivative. Discrete areas of the back were irradiated with low doses of ssUV daily for three consecutive days. Immunosuppression, calculated as the difference in Mantoux-induced erythema of irradiated sites compared with unirradiated control sites, was determined in volunteers taking oral nicotinamide and placebo. Significant immunosuppression occurred in an UV dose-dependent manner in the presence of placebo. Oral nicotinamide, at doses of either 1500 or 500 mg daily, was well tolerated and significantly reduced UV immunosuppression with no immune effects in unirradiated skin. Oral nicotinamide is safe and inexpensive and looks promising as a chemopreventive supplement for reducing the immunosuppressive effects of sunlight.

Broad-spectrum sunscreens provide better protection from solar ultraviolet–simulated radiation and natural sunlight–induced immunosuppression in human beings

It is well established that ultraviolet (UV) radiation induces immunomodulatory effects that may be involved in skin cancer. Recent studies have shown that UVA (320-400 nm) and UVB (290-320 nm) radiation are immunosuppressive. As a result, sunscreens, which mainly absorb UVB, may be less effective in preventing UV radiation-induced immunosuppression than broad-spectrum products. We sought to study the effects of UVA exposure on human delayed-type hypersensitivity (DTH) response and compare the efficacy of sunscreens having different levels of sun-protection factor (SPF) and UVA protection against both solar-simulated radiation and outdoor real-life sunlight exposure conditions. DTH was assessed using a kit which includes 7 recall antigens that most of the participants encountered during childhood immunization. Evaluation of DTH test response was made 48 hours after test application before and after UV exposure with or without sunscreens. In unprotected participants, the response to DTH tests was significantly reduced irrespective of UV types of exposure (full-spectrum UVA, long UVA, solar-simulated radiation). A UVB sunscreen failed to protect from solar-simulated radiation-induced immunosuppression. In contrast, a broad-spectrum sunscreen with the same SPF but providing a high protection in the UVA range significantly reduced local UV-induced immunosuppression and prevented the distant effects. In the outdoor study, as compared with DTH responses obtained before sun exposure, no alteration of immune response was detected when the skin was protected by a broad-spectrum sunscreen having a high protection level in the UVA (SPF 25, UVA protection factor 14). Conversely a broad-spectrum sunscreen with lower protection against UVA (SPF 25, UVA protection factor 6) failed to prevent UV-impaired response. These results have been obtained after repeated exposure. Additional experiments obtained under acute exposure are in progress. These findings clearly demonstrated the role of UVA in the induction of photoimmunosuppression together with the need for sunscreen products providing efficient photoprotection throughout the entire UV spectrum.

Resistance of a Lizard (the Green Anole, Anolis carolinensis; Polychridae) to Ultraviolet Radiation-induced Immunosuppression¶

Resistance of a Lizard (the Green Anole, Anolis carolinensis; Polychridae) to Ultraviolet Radiation-induced Immunosuppression¶

A single sub‐erythematous exposure of solar‐simulated radiation on the elicitation phase of contact hypersensitivity induces IL‐10‐producing T‐regulatory cells in human skin

Solar ultraviolet (UV) radiation has hazardous effects on human health that are, in part, associated with its immunosuppressive effects via the induction of interleukin (IL)-10 production. Although IL-10 is produced by both T helper type 2 (Th2) cells and T-regulatory type 1 (Tr1) cells, the relative contribution of either subset in UV radiation-induced immunosuppression has not been established. Here, we show that T cells isolated from non-treated allergic contact dermatitis (ACD) reactions, 48 h following nickel challenge and propagated for 7-10 days in the presence of IL-2, were mainly CD4(+) and produced IL-10, but little interferon-gamma. A single sub-erythematous solar-simulated radiation (SSR) prior to antigen challenge exposure resulted in a clinical attenuation of the intensity of ACD reactions which was associated with a significant increase in both the magnitude of IL-10 production by skin-infiltrating T cells and the frequency of IL-10-producing Tr1 cells. Skin-infiltrating T cells in SSR-exposed, as well as non-exposed, ACD reactions showed a perturbed T-cell receptor (TCR)-Vbeta repertoire, without overexpression of a particular TCR-Vbeta gene product, indicating the presence of high frequencies of nickel non-specific T cells in ACD reactions. These results show that a single sub-erythematous SSR induces immunosuppression via the cutaneous infiltration of IL-10-producing Tr1, and to a lesser extent, Th2 cells.

Spectral and dose dependence of ultraviolet radiation-induced immunosuppression

Ultraviolet radiation (UV) wavelength and dose dependence has been demonstrated for a number of cutaneous endpoints such as erythema, pigment darkening, DNA damage, and photocarcinogenesis. More recently, a number of in-vitro and in-vivo models of UV immunosuppression have implicated UVA (320-400 nm) in immune protection as well as immune suppression. While the wavelength dependencies for immunosuppression within UVB have been well established in mice, the exact role of specific UVA wavelengths has been less clear. Moreover, in humans, the spectral dependence of UV immunosuppression is even less well established. This review firstly outlines the established UV action spectra for a variety of cutaneous effects. The waveband and dose dependence of UV immunosuppression and its mechanisms are explored with a focus on in-vivo models. Finally, since UV immunosuppression along with DNA damage is thought to play a central role in the development of skin cancer, a clearer understanding of the immunosuppressive potential of discrete UV wavebands will allow a more rational approach to our understanding and prevention of skin cancer.

Tamarind Inhibits Solar-Simulated Ultraviolet Radiation-Induced Suppression of Recall Responses in Humans

To determine whether topically applied biologically active drugs can be used to protect the human immune system from sunlight, we studied the effect of tamarind xyloglucan polysaccharide, a natural and common fruit constituent, on solar-simulated, ultraviolet radiation-induced local immunosuppression and erythema in humans. Immunosuppression was studied in humans using a nickel contact hypersensitivity recall model. Ultraviolet dose responses were generated to determine the extent to which tamarind affected the immune response in a group of 15 volunteers. The subsequent nickel-induced erythema was quantitated using a reflectance spectrometer. 0.1 μgml-1 of topical tamarind polysaccharide reduced ultraviolet radiation-induced immunosuppression. Frozen sections of biopsies taken were analysed by immunohistochemistry. Tamarind inhibited ultraviolet radiation-induced CD11c+ dendritic cell loss from the epidermis. The ultraviolet doses used in this study did not alter the number of Mac387+ macrophages or NP57+ neutrophils infiltrating the skin. Low dose xyloglucan polysaccharide from tamarind protected from immunosuppression in humans, possibly by reducing ultraviolet radiation-induced loss of dendritic cells, demonstrating that these types of drugs may be useful adjuncts to sunscreens for protection from skin cancer. Keywords: tolerance, skin, dendritic cells, tumour immunity, ultraviolet, sunlight

Dietary lutein reduces ultraviolet radiation-induced inflammation and immunosuppression.

Ultraviolet radiation (UVR) promotes skin cancer development by mutagenic, immunosuppressive, and oxidative-stress-inducing mechanisms; however, certain antioxidants may counteract and prevent UVR-induced photodamage. Lutein is a xanthophyll carotenoid with potent antioxidant activity. Because reactive oxygen species (ROS) are believed to have a role in UVR-induced skin damage, we investigated whether lutein can modify UVR effects including the tissue swelling response to midrange UVR (280-320 nm, ultraviolet B (UVB) radiation) and UVB suppression of contact hypersensitivity (CHS) in both the local and the systemic models of UV-induced immunosuppression. We found that compared to mice fed the standard laboratory diet, mice fed dietary lutein demonstrated significant inhibition of ear swelling owing to UVB radiation. Mice exposed to 1700 J per m2 UVB radiation four times at daily intervals and then sensitized to dinitrofluorobenzene at the site of irradiation showed a decreased CHS response upon challenge. This suppression by UVB radiation was significantly inhibited by lutein feeding. When UVB radiation was given at a single dose of 10,000 J per m2 to inhibit the induction of CHS at a distant, nonirradiated site, no effect of lutein was seen. Finally, lutein accumulated in the skin of mice following diet supplementation and was shown to decrease ROS generation following UVR exposure. Thus, lutein modulates the skin's response to UVR and may contribute to the defense against some of the deleterious effects of solar radiation.

Nitric oxide appears to be a mediator of solar-simulated ultraviolet radiation-induced immunosuppression in humans.

Topical application of NG-methyl-L-arginine and 2,2'-dipyridyl were used to examine the respective roles of nitric oxide and reactive oxygen species in solar-simulated ultraviolet radiation-induced immunosuppression in humans in vivo. Immunosuppression was studied using a nickel contact hypersensitivity recall model. Ultraviolet radiation dose-responses were generated to determine the extent to which NG-methyl-L-arginine and 2,2'-dipyridyl affected the immune response. NG-methyl-L-arginine but not 2,2'-dipyridyl protected the immune system from ultraviolet radiation-induced suppression. Both NG-methyl-L-arginine and 2,2'-dipyridyl inhibited nitrite production. Nitrite is a degradation product of peroxynitrite, a cytotoxic mediator resulting from reactions between nitric oxide and reactive oxygen species. This suggests that nitric oxide, not its downstream product peroxynitrite, was likely to be responsible for solar-simulated ultraviolet radiation-induced immunosuppression. In contrast, both nitric oxide and reactive oxygen species were mediators of solar-simulated ultraviolet radiation-induced apoptosis and loss of dendritic S-100+ cells (probably Langerhans cells) from the epidermis. It is likely that different mechanisms are involved in these ultraviolet-induced endpoints and that events in addition to Langerhans cell depletion are important for local immune suppression to recall antigens in humans. Understanding the mechanisms of cutaneous ultraviolet-induced oxidative stress will assist in the future design of novel products that protect skin from photoaging and skin cancer.

A commercial sunscreen's protection against ultraviolet radiation-induced immunosuppression is more than 50% lower than protection against sunburn in humans.

Ultraviolet radiation (280-400 nm)-induced suppression of cutaneous cell-mediated immunity plays an important part in the development of skin cancer. Sunscreens are widely advocated to protect against skin cancer but if they offer insufficient protection against immunosuppression they may inadvertently increase skin cancer risk. This human study evaluated immunoprotection afforded by a commercial sunscreen preparation (labeled sun protection factor 15) offering primarily ultraviolet B (280-320 nm) protection. Indirectly, it also investigated whether ultraviolet A (320-400 nm) plays a part in ultraviolet radiation-induced immunosuppression. Healthy white-skinned volunteers were used (n=119). Ultraviolet radiation exposures were on previously unexposed buttock skin with an ultraviolet radiation source that complied with European recommendations for sunscreen testing. Ultraviolet radiation dose-response curves for sunburn/erythema and suppression of the contact hypersensitivity response were generated either with or without sunscreen in vivo and protection factors were derived for both end-points. The ultraviolet radiation wavelengths transmitted by the sunscreen were determined in vitro and showed that the sunscreen was primarily an ultraviolet B absorber, with relatively poor absorption in the ultraviolet A region. The sun-screen protected against both erythema and immunosuppression but protection against immunosuppression (IPF=4.9, 95% confidence interval: 2.3-10.6) was less than half that for erythema (Ery-PFg=14.2, 95% confidence interval: 10.2-19.8). Failure of the sunscreen to afford comparable protection against both end-points was probably due to immunosuppression by ultraviolet A, a part of the solar spectrum that does not readily cause sunburn. The sunscreen protected against both end-points, which supports the use of sunscreens to reduce immunosuppression but protection against immunosuppression may be improved if sunscreens are formulated to offer equivalent protection against ultraviolet B and ultraviolet A.

Neuropeptides and neuroendocrine hormones in ultraviolet radiation-induced immunosuppression

Exposure of the skin to ultraviolet radiation (UVR) can lead to deleterious effects such as sunburn, photoaging, and the development of skin cancer. UVR has also been shown to reduce local and systemic immune responses in humans and animals. In the recent past it has become clear that neuropeptides mediate some of the effects of UVR-induced immunosuppression. Among the neuropeptides released from cutaneous nerves after exposure to UVR, calcitonin gene-related peptide (CGRP) has been examined most extensively. It appears to lead to a reduction of contact hypersensitivity by inducing mast cells to degranulate and thus release tumor necrosis factor α (TNF-α) and, most likely, interleukin (IL)-10. Nitric oxide, which is coreleased with CGRP, seems to also play a role in immunosuppression through a yet undiscovered mechanism of action, while substance P may have counterregulatory effects. New evidence suggests that the release of neuropeptides from cutaneous sensory c-fibers after UVR is induced by keratinocyte-derived nerve growth factor. UVR can also induce epidermal and some dermal cells, such as melanocytes, keratinocytes, and dermal microvascular epithelial cells, to produce proopiomelanocortin (POMC) and its derivatives. The POMC product α-melanocyte-stimulating hormone (α-MSH) has been implicated in suppression of contact hypersensitivity and induction of hapten-specific tolerance, most likely by inducing keratinocytes and monocytes to produce the anti-inflammatory cytokine IL-10. Other POMC derivatives have not yet been investigated with regard to a possible role in UVR-induced effects on immunity.