Mast cells in UV-B-induced immunosuppression

Degranulating dermal mast cells in UV-B-irradiated skin have been implicated for many years in the mechanisms of irradiation erythema. There is now considerable evidence that dermal mast cells are important to the processes by which both UV-B radiation and cis-urocanic acid (cis-UCA) suppress immune responses to sensitizing antigens applied to non-irradiated/non-cis-UCA-exposed sites. Mast-cell-depleted mice are resistant to the immunosuppressive effects of UV-B radiation and cis-UCA for 'systemic' immunomodulation. However, these mice gain responsiveness if the dorsal skin is reconstituted six weeks prior to irradiation or cis-UCA administration at that site with cultured bone-marrow-derived mast cells from +/+ mice. The molecular triggers for initiating mast-cell degranulation are being actively sought. Evidence suggests that histamine, and not tumour necrosis factor alpha, is the major mast-cell product that signals altered immune responses to sensitizing antigens applied to non-irradiated, non-cis-UCA-exposed sites. Histamine may have multiple roles, but experiments with indomethacin administered to mice have shown that one process involves induction of prostanoid production.     

UVA exposure affects UVB and cis-urocanic acid-induced systemic suppression of immune responses in Listeria monocytogenes-infected Balb/c mice

Ultraviolet radiation can inhibit immune responses locally as well as systemically. Such effects have been measured in animals and humans exposed to ultraviolet B (wavelength 280-315 nm) (UVB) and ultraviolet A (315-400 nm) (UVA). The precise wavelength dependence is important for the identification of possible molecular targets and for assessments of risk of different artificial UV sources and solar UV. In such analyses, it is commonly assumed that radiation energy from each wavelength contributes to the effect independent of the other wavelengths. Here we show that this assumption does not hold good. In the present study, it was investigated whether exposure to broadband UVA or longwave ultraviolet A 1 (340-400 nm) (UVA 1) prior to the standard immunosuppressive UVB protocol might modulate the immunosuppressive effects induced by UVB. Preexposure to broadband UVA or longwave UVA 1, 1 day prior to the standard immunosuppressive UVB protocol, inhibited the UVB-induced suppression of delayed type hypersensitivity (DTH) to Listeria monocytogenes significantly. This effect was not associated with restoring the number of interleukin (IL-12)-positive cells in the spleen. Since isomerization of trans-urocanic acid (UCA) into the immunosuppressive cis-UCA isomer plays a crucial role in UVB-induced immunomodulation, in a second set of experiments it was investigated whether immunosuppression induced by cis-UCA might also be downregulated by preexposure to UVA. Animals were exposed to broad-band UVA or longwave UVA 1 prior to application of an immunosuppressive dose of cis- or trans-UCA as a control. Both UVA and UVA 1 appear to inhibit the cis-UCA-induced systemic immunosuppression (DTH and IL-12) to L. monocytogenes. These studies clearly show that UVA radiation modulates both UVB and cis-UCA-induced immunomodulation. In general, our studies indicate that both broadband UVA and longwave UVA 1 could induce modulation of UVB and cis-UCA-induced immunomodulation. As sunlight contains both UVA and UVB radiation the balance between these two radiations apparently determines the net immunomodulatory effect.     

UVB exposure impairs immune responses after hepatitis B vaccination in two different mouse strains

Ultraviolet light exposure can impair immune responses that are not restricted to the exposed skin but is also found at other sites, i.e. systemic immunosuppression. Therefore, we investigated the UV-induced modulating effects on vaccination against hepatitis B in a mouse model. Two different mouse strains, BALB/c and C57B1/ 6, were vaccinated intramuscularly against hepatitis B. Mice were exposed to different doses of ultraviolet B (UVB) for five consecutive days on shaved back skin before the vaccination. Vaccination against hepatitis B induced cellular (delayed-type hypersensitivity [DTH] and lymphocyte stimulation test) as well as humoral immune responses in both mouse strains. The DTH responses in C57BB1/6 mice were statistically significantly higher compared with BALB/c mice. UVB exposure induced a dose-dependent suppression of cellular immunity in both strains of mice. C57B1/6 mice seemed to be more susceptible to this suppression. Anti-hepatitis B surface antibodies (total-Ig) were only marginally suppressed after UVB exposure. IgG2a and interferon-gamma levels, both indicators for Th1 immune response, were suppressed in both mouse strains after UVB exposure. In summary, UVB exposure induced a dose-dependent suppression of both cellular and humoral immune responses after hepatitis B vaccination, although the suppressive effects on humoral immunity were limited to IgG2a production. Susceptibility to UVB-induced immunomodulation depended on the strain of mice and their predilection for developing different T cell responses.     

The Protective Effect of N-Acetylcysteine on UVB-Induced Immunosuppression by Inhibition of the Action of Cis-Urocanic Acid

Abstract— A recent study has shown that N-acetylcysteine (NAC) not only has sun-protective properties but also inhibits the UVB-induced suppression of contact hypersensitivity (CHS) in mice. Because NAC does not absorb any UVA (320-400 nm radiation) or UVB (290-320 nm radiation) we have studied the underlying mechanism of protection. Irradiation of solutions of plasmid DNA with UVC (200-290 nm radiation) (10 J m-2) resulted in the formation of cyclobutane pyrimidine dimers, but the extent to which this occurred was not affected by the presence of NAC as was determined by an in vitro T4 endonuclease assay. N-acetylcysteine proved not to have any effect on the photoisomerization of trans-urocanic acid (UCA) to its cis-form in vitro; at equilibrium, approximately 55% cis-UCA was formed. The same percentage was also found in vivo on exposure of mice to UVB (15 kj m-2). Topical application of NAC 30 min prior to irradiation did not have any influence as well on the photoisomerization of trans- to cis-UCA. These in vivo experiments were performed under the same conditions used previously to show the protective effect of NAC against UVB-induced suppression of CHS.
We conclude that this protection of NAC is at least partly based on interference in the role of cis -UCA in UVB-induced suppression of CHS. This conclusion is supported by the observation that NAC completely inhibits the suppression of CHS by cis -UCA administered to mice that were always kept in the dark. In the same range of doses as used in the present study, it was shown in our previous study that NAC alone does not affect the CHS response.     

Suppression of an established immune response by UVA--a critical role for mast cells

Exposing experimental animals or human volunteers to UVA II (320-340 nm) radiation after immunization suppresses immunologic memory and the elicitation of delayed-in-time hypersensitivity reactions. Previous studies indicated that the mechanisms underlying UVA-induced immune suppression are similar to those described for UVB-induced immune suppression, i.e. transferred by T regulatory cells, overcome by repairing DNA damage, neutralizing interleukin (IL)-10 activity, or injecting recombinant IL-12. Here we continued our examination of the mechanisms involved in UVA II-induced suppression. Antibodies to cis-urocanic acid blocked UVA-induced immune suppression. Treating UVA-irradiated mice with histamine receptor antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists or platelet activating factor receptor antagonists blocked immune suppression in UVA-irradiated mice. In light of the fact that cis-urocanic acid and CGRP target mast cells, which can then release platelet activating factor and histamine, we measured UVA-induced immune suppression in mast cell-deficient mice. No immune suppression was noted in UVA-irradiated mast cell-deficient mice. These findings indicate that exposure to UVA II activates many of the same immune regulatory factors activated by UVB to induce immune suppression. Moreover, they indicate that mast cells play a critical role in UVA-induced suppression of secondary immune reactions.     

A GARLIC EXTRACT PROTECTS FROM ULTRAVIOLET B (280–320 nm) RADIATION-INDUCED SUPPRESSION OF CONTACT HYPERSENSITIVITY

Abstract Lyophilized aged garlic extract has been incorporated at concentrations of 0.1%, 1% and 4% by weight into semipurified powdered diets and fed to hairless mice. Under moderate UVB exposure conditions resulting in 58% suppression of the systemic contact hypersensitivity response in control-fed mice, a dose-responsive protection was observed in the garlic-fed mice; contact hypersensitivity in the UVB-exposed mice fed 4% garlic extract was suppressed by only 19%. If the UVB exposure was replaced by topical application of one of a series of lotions containing increasing concentrations of cis -urocanic acid, a dose-responsive suppression of contact hypersensitivity was demonstrated in control-fed mice (urocanic acid at 25, 50, 100 and 200 μg per mouse resulting in 22–46% suppression). Mice fed a diet containing 1% aged garlic extract were partially protected from cis -urocanic acid-induced suppression of contact hypersensitivity, with greater protection from the lower concentrations of urocanic acid. Mice fed a diet containing 4% aged garlic extract were protected from all concentrations of urocanic acid. The results indicate that aged garlic extract contains ingredient(s) that protect from UVB-induced suppression of contact hypersensitivity and suggest that the mechanism of protection is by antagonism of the cis -urocanic acid mediation of this form of immunosuppression.     

Cis-UROCANIC ACID DOWN-REGULATES THE INDUCTION OF ADENOSINE 3'', 5''-CYCLIC MONOPHOSPHATE BY EITHER trans-UROCANIC ACID OR HISTAMINE IN HUMAN DERMAL FIBROBLASTS in vitro

It has been demonstrated that UVB radiation (290-320 nm) suppresses mammalian cell-mediated immunity by effecting the trans to cis isomerization of urocanic acid (UCA) in the stratum corneum, the uppermost layer of the skin. Trans-urocanic acid has been shown to be the photoreceptor for UVB-induced immune suppression and the cis-isomer has been demonstrated to be immunosuppressive. Little is known, however, about how the isomerization of UCA may affect the proximal or distal cells of the skin or the immune system. We report here that trans-UCA is biologically active in vitro in human dermal fibroblasts, inducing adenyl cyclase as measured by cAMP (adenosine 3',5'-cyclic monophosphate) formation in a dose-dependent manner similar to the action of histamine. Trans-UCA and histamine stimulate 50% of maximum activity at concentrations of 3.3 microM and 13.8 microM respectively. Cis-UCA does not increase cAMP in these human fibroblasts but actively down regulates the increase of cAMP induced by either histamine or trans-UCA. Cis-UCA down regulated the histamine response by 75% and the trans-UCA response by 60% at a concentration range of 1 mM to 1 nM. The trans-UCA induction of cAMP can also be downregulated with an H2 histamine receptor antagonist cimetidine. These results support the hypothesis that a cellular target for cis-UCA is the dermal fibroblast and the effects reported here may represent the initial biochemical and cellular event for UVB-induced immune suppression i.e. the immediate step following the isomerization of trans to cis-UCA is the down regulation of cAMP by cis-UCA. Regulation of such an important second messenger such as cAMP could then allow cascading signals to occur, leading to immune suppression.     

Topically applied eicosapentaenoic acid protects against local immunosuppression induced by UVB irradiation, cis-urocanic acid and thymidine dinucleotides

UVB-induced immunosuppression, a promoter of photocarcinogenesis, involves the formation of pyrimidine dimers and cis-urocanic acid (cis-UCA), but reactive oxygen species (ROS) also plays an important role. Eicosapentaenoic acid (EPA) can inhibit photocarcinogenesis, but due to its polyunsaturated nature it is susceptible to oxidative damage by ROS. The antioxidant defense system may therefore be challenged upon ultraviolet-B (UVB) irradiation in the presence of EPA. We investigated whether topically applied EPA in mice could protect against local immunosuppression (contact hypersensitivity response to dinitrofluorobenzene) induced by UVB radiation (1.5 J/cm2), or topically applied cis-UCA (150 nmol/cm2) or thymidine dinucleotides (pTpT) (5 nmol/cm2). The influence of EPA on epidermal lipid peroxidation and antioxidant status was also measured. UVB irradiation, cis-UCA and pTpT all caused 70% immunosuppression. Topical pretreatment of mice with EPA partially protected against immunosuppression; the EPA dose needed to accomplish this was 10 nmol/cm2 for UVB irradiation, 100 nmol/cm2 for cis-UCA and 1000 nmol/cm2 for pTpT. Higher EPA doses caused higher UVB-induced lipid peroxidation and lower vitamin C levels. Glutathione only decreased with the highest EPA dose whereas vitamin E was not decreased after UVB irradiation. In conclusion, topically applied EPA protects against UVB-, cis-UCA- and pTpT-induced immunosuppression and maintenance of an adequate antioxidant defense seems to be an important prerequisite for the protective action by EPA.     

Green tea polyphenols: DNA photodamage and photoimmunology.

Green tea is a popular beverage consumed worldwide. The epicatechin derivatives, which are commonly called 'polyphenols', are the active ingredients in green tea and possess antioxidant, anti-inflammatory and anti-carcinogenic properties. Studies conducted by our group on human skin have demonstrated that green tea polyphenols (GTP) prevent ultraviolet (UV)-B-induced cyclobutane pyrimidine dimers (CPD), which are considered to be mediators of UVB-induced immune suppression and skin cancer induction. GTP treated human skin prevented penetration of UV radiation, which was demonstrated by the absence of immunostaining for CPD in the reticular dermis. The topical application of GTP or its most potent chemopreventive constituent (-)-epigallocatechin-3-gallate (EGCG) prior to exposure to UVB protects against UVB-induced local as well as systemic immune suppression in laboratory animals. Additionally, studies have shown that EGCG treatment of mouse skin inhibits UVB-induced infiltration of CD11b+ cells. CD11b is a cell surface marker for activated macrophages and neutrophils, which are associated with induction of UVB-induced suppression of contact hypersensitivity responses. EGCG treatment also results in reduction of the UVB-induced immunoregulatory cytokine interleukin (IL)-10 in skin as well as in draining lymph nodes, and an elevated amount of IL-12 in draining lymph nodes. These in vivo observations suggest that GTPs are photoprotective, and can be used as pharmacological agents for the prevention of solar UVB light-induced skin disorders associated with immune suppression and DNA damage.     

Viability of the antigen determines whether DNA or urocanic acid act as initiator molecules for UV-induced suppression of delayed-type hypersensitivity

UV radiation suppresses the immune response, and UV-induced immune suppression contributes to UV-induced photocarcinogenesis. For UV-induced immune suppression to occur, electromagnetic energy (i.e. UV radiation) must be converted to a biological signal. Two photoreceptors have been identified in the skin that serves this purpose, epidermal DNA and trans-urocanic acid (UCA). Although compelling evidence exists to support a role for each pathway (UV-induced DNA damage or photoisomerization of UCA) in UV-induced immune suppression, it is not clear what determines which photoreceptor pathway is activated. To address this question, we injected UV-irradiated mice with a monoclonal antibody with specificity for cis-UCA or applied liposomes containing DNA repair enzymes to the skin of UV-irradiated mice. The effect that each had on UV-induced suppression of delayed-type hypersensitivity was measured. We asked whether the light source used (FS-40 sunlamps vs solar-simulated UV radiation) altered whichever pathway of immune suppression was activated. Different doses of UV radiation and the viability of the antigen were also considered. Neither the dose of UV nor the light source had any influence on determining which pathway was activated. Rather, we found that the viability of the antigen was the critical determinant. When live antigens were used, UV-induced immune suppression was blocked with monoclonal anti-cis-UCA but not with T4 endonuclease V-containing liposomes. The reverse was observed when formalin-fixed or killed antigens were used. Our findings indicate that antigen viability dictates which photoreceptor pathway predominates after UV exposure.     

Radiation sources providing increased UVA/UVB ratios induce photoprotection dependent on the UVA dose in hairless mice

In studies involving mice in which doses of UVA (320-400 nm) and UVB (290-320 nm) radiation were administered alone or combined sequentially, we observed a protective effect of UVA against UVB-induced erythema/edema and systemic suppression of contact hypersensitivity. The UVA immunoprotection was mediated by the induction of the stress enzyme heme oxygenase-1 (HO-1) in the skin, protection of the cutaneous Th1 cytokines interferon-gamma (IFN-gamma) and IL-12 and inhibition of the UVB-induced expression of the Th2 cytokine IL-10. In this study, we seek evidence for an immunological waveband interaction when UVA and UVB are administered concurrently to hairless mice as occurs during sunlight exposure in humans. A series of spectra providing varying ratios of UVA/UVB were developed, with the UVA ratio increased to approximately 3.5 times the UVA component in solar simulated UV (SSUV). We report that progressively increasing the UVA component of the radiation while maintaining a constant UVB dose resulted in a reduction of both the erythema/edema reaction and the degree of systemic immunosuppression, as measured as contact hypersensitivity. The UVA-enhanced immunoprotection was abrogated in mice treated with a specific HO enzyme inhibitor. UVA-enhanced radiation also upregulated the expression of cutaneous IFN-gamma and IL-12 and inhibited expression of both IL-6 and IL-10, compared with the activity of SSUV. The results were consistent with the previously characterized mechanisms of photoprotection by the UVA waveband alone and suggest that the UVA component of solar UV may have beneficial properties for humans.     

Platelet-activating factor does not mediate UVB-induced local immune suppression

The lipid mediator Platelet-activating factor (PAF) and oxidized glycerophosphocholine PAF agonists produced by UVB have been demonstrated to play a pivotal role in UVB-mediated systemic immunosuppression. Importantly, employing the ability of distant UVB irradiation to inhibit contact hypersensitivity (CHS) responses to the chemical antigen dinitrofluorobenzene (DNFB) to an area of unirradiated murine skin, we and others have demonstrated that UVB-mediated systemic immunosuppression was only observed in PAF-R expressing wild type (WT) mice and not in PAF-R-knockout (Pafr-/-) mice. As it is not known if PAF is involved in UVB-mediated local immunosuppression, these studies compared local UVB on CHS responses in WT versus Pafr-/- mice. We demonstrate that the application of DNFB onto UVB-exposed (locally) area of mouse skin resulted in a similar significant inhibition of subsequent CHS responses in both WT and Pafr-/- mice compared to sham-irradiated control mice. Furthermore, the expression of langerin, a marker for the presence of Langerhans cells was substantially reduced equally in the epidermal ears of UVB-irradiated WT and Pafr-/- mice compared to their respective sham control groups. These findings indicate that the PAF-R is not involved UVB-induced local immunosuppression.     

PROTECTION AGAINST ULTRAVIOLET-B RADIATION-INDUCED LOCAL and SYSTEMIC SUPPRESSION OF CONTACT HYPERSENSITIVITY and EDEMA RESPONSES IN C3H/HeN MICE BY GREEN TEA POLYPHENOLS

Abstract— Exposure of skin to UV radiation can cause diverse biological effects, including induction of inflammation, alteration in cutaneous immune cells and impairment of contact hypersensitivity (CHS) responses. Our laboratory has demonstrated that oral feeding as well as topical application of a poly-phenolic fraction isolated from green tea (GTP) affords protection against the carcinogenic effects of UVB (280–320 nm) radiation. In this study, we investigated whether GTP could protect against UVB-induced immunosuppression and cutaneous inflammatory responses in C3H mice. Immunosuppression was assessed by contact sensitization with 2,4-dinitrofluorobenzene applied to UVB-irradiated skin (local suppression) or to a distant site (systemic suppression), while double skin-fold swelling was used as the measure of UVB-induced inflammation. Topical application of GTP (1–6 mg/animal), 30 min prior to or 30 min after exposure to a single dose of UVB (2 kj/m²) resulted in significant protection against local (25–90%) and systemic suppression (23–95%) of CHS and inflammation in mouse dorsal skin (70–80%). These protective effects were dependent on the dose of GTP employed; increasing the dose (1–6 mg/animal) resulted in an increased protective effect (25–93%). The protective effects were also dependent on the dose of UVB (2–32 kJ/m²). Among the four major epicatechin derivatives present in GTP, (‐)-epigallocatechin-3-gallate, the major constituent in GTP, was found to be the most effective in affording protection against UVB-caused CHS and inflammatory responses. Our study suggests that green tea, specifically polyphenols present therein, may be useful against inflammatory dermatoses and immunosuppression caused by solar radiation.     

Susceptibility to basal cell carcinoma is associated with high dermal mast cell prevalence in non-sun-exposed skin for an Australian populations

In a Danish population, basal cell carcinoma (BCC) patients have a higher dermal mast cell prevalence in buttock skin than controls. This finding was supported by a functional link in mice between histamine-staining dermal mast cells and the extent of susceptibility to UV-B-induced systemic immunomodulation. It was important to confirm that this association was maintained in an Australian population with very different ancestry and sun exposure patterns. Australian BCC patients (n = 26) had significantly higher densities of mast cells in the dermis of buttock skin than control subjects (n = 25) (P = 0.0003, Mann-Whitney U-test). However, this correlation was lost at the sun-exposed site of the hand (P = 0.547, Mann-Whitney U-test). To further evaluate whether a relationship exists between dermal mast cell prevalence in sun-exposed skin and incidence of BCC in a larger study, biopsies of dorsal hand skin were obtained from an age-stratified random sample of 166 Queensland subjects, together with the 51 South Australian subjects, and dermal mast cell prevalence was quantified. Older subjects (over the median age of 42 years) had a greater incidence of BCC development (P = 0.0001, chi-square test) and significantly higher mast cell densities in hand skin (P = 0.0001, chi-square test) than younger subjects. However, mast cell density in sun-exposed hand skin was not significantly associated with BCC incidence. Finally, cellular expression of c-kit correlated with mast cell prevalence in non-sun-exposed skin, thereby implicating the stem cell factor-c-kit axis in the intrinsic mechanisms that regulate prevalence. These results show that high prevalence of dermal mast cells in buttock skin but not hand is associated with BCC development in an Australian population.     

Suppression of Delayed and Contact Hypersensitivity Responses in Mice Have Different UV Dose Responses

Although acute exposure to UV radiation suppresses the induction of delayed-type (DTH) and contact (CHS) hypersensitivity in mice, it is not clear whether the photo-biological mechanism(s) involved in suppressing these closely related immune reactions is the same. A careful examination of the UV dose responses and wavelength dependencies involved in suppressing CHS and DTH may provide important insights into the mechanisms involved. We compared the UV dose-response curves for suppressing four closely related immune reactions, local and systemic suppression of CHS to dinitrofluorobenzene, systemic suppression of DTH to Candida albicans and systemic suppression of DTH to alloantigen using three different UV spectra (FS40 sunlamps, Kodacel-filtered FS40 sunlamps and solar-simulated light). For each immune response studied, the amount of UVB radiation required to induce 50% immune suppression was lowest when FS40 sunlamps were used, highest with solar-simulated light and intermediate when Kodacel-filtered FS40 sunlamps were used, but the differences observed were not statistically significant. The UV dose-response curves for immune suppression differed significantly depending on the assay used, the site of antigenic sensitization and the antigen used. These findings suggest that the mechanisms by which UV radiation induces immune suppression differ for the four immunological reactions studied.     

A Role for Neuropeptides in UVB-Induced Systemic Immunosuppression

The aim of this study was to investigate the possible role of sensory nerves in UV light-induced systemic immunomodulation. Contact hypersensitivity to the low molecular weight compound picrylchloride was used as a model for cellular immunity that can be suppressed by low (i.e. suberythemal) doses of UV light even after exposure at a distant locus (i.e. systemic immunosuppression). In sensory nerve-depleted mice, achieved by two subcutaneous injections with the neurotoxin capsaicin before the age of 4 weeks, UV light exposure failed to inhibit contact hypersensitivity responses to picrylchloride. This indicates that sensory nerves are at least partially involved in the induction of systemic immunosuppression by UV light. In order to analyze whether sensory neuropeptides, such as calcitonin gene-related peptide (CGRP) and tachykinins, are involved in UV light-induced systemic immunosuppression, mice were pretreated with selective antagonists prior to each UV light exposure. These experiments indicated that CGRP but not the tachykinins plays a crucial role in the UV light-induced systemic immunosuppression.     

Mechanism of UVB-Induced Suppression of the Immune Response to Mycobacterium bovis Bacillus Calmette-Guerin: Role of Cytokines on Macrophage Function

Previously we demonstrated that treatment of mice with either UVB radiation or supernatants derived from UVB-irradiated PAM 212 keratinocytes decreased the induction of the delayed-type hypersensitivity (DTH) response to Mycobacterium bovis bacillus Calmette-Guerin (BCG), impaired the clearance of bacteria from their lymphoid organs and also altered macrophage functions. In order to characterize the cytokines involved in these phenomena, UV-irradiated mice were injected with antibodies to interleukin-10 (IL-10), transforming growth factor-β1 (TGF-β1), or tumor necrosis factor-α (TNF-α). Injection of UVB-irradiated mice with anti-IL-10 immediately after UV irradiation restored the DTH response and reversed the UV-induced inhibition of bacterial clearance. Injection of UV-irradiated mice with anti-TGF-β only partially restored the DTH response although it allowed a better clearance of BCG than injection of mice with the control antibody. In contrast, injection of anti-TNF-α did not affect the UVB-induced suppression of DTH or impaired bacterial clearance. Similarly, the ability of macrophages to phagocytose BCG and kill the intracellular organisms was restored to almost normal levels after injecting UV-irradiated mice with antibodies specific for IL-10 or TGF-β. Injection of mice with either recombinant IL-10 or TGF-β mimicked the effect of whole-body UV irradiation on immune function. These results suggest that IL-10 has a major role in UV-induced suppression of both DTH to BCG and impairment in the clearance of bacteria and that TGF-β has a more significant role in blocking bacterial clearance. Furthermore, these cytokines seem to modulate immune responses by altering macrophage functions in UVB-irradiated mice.     

Protection against photoaging in the hairless mouse by the isoflavone equol

Topical application of the isoflavone equol immediately following solar-simulated UV (SSUV) radiation exposure has previously been demonstrated to have significant photoprotective effects. Equol reduced both the inflammatory edema and the systemic suppression of the contact hypersensitivity reaction in hairless mice. Furthermore, daily topical equol application immediately following irradiation during a 10-week chronic SSUV exposure regime also reduced photocarcinogenesis severity in the mouse. This study examines the potential for topical equol to prevent photoaging in response to chronic SSUV irradiation for up to 30 weeks. We did not find consistent expression of the characteristic markers of photoaging until 30 weeks, although moderate epidermal hyperplasia and a transient increase in dermal mast cell numbers were evident after 1 week. Daily application of 10 muM equol lotion significantly reduced these early changes. However after 30 weeks of SSUV exposure, photoaging was well developed, as shown histologically by markedly increased epidermal hyperplasia, increased dermal mast cell number, pronounced focal elastotic deposits, degraded dermal collagen and deposition of glycosaminoglycans in the lower dermis. Topical equol treatment protected significantly from each of these impairments, as demonstrated histologically and quantitatively. Additionally, equol was found to have strong antioxidant action against acute UVA (320-400 nm)-induced lipid peroxidation of mouse skin, this property accounting for its antiphotoaging mechanism. The evidence for equol's antiphotoaging activity, taken together with its anti-inflammatory, immunoprotective and anticarcinogenic efficacy against SSUV irradiation in the mouse, suggests that equol could be developed as a helpful topical photoprotective agent for daily use by humans.     

The effect of UV irradiation on infection of mice with Borrelia burgdorferi

These studies addressed the hypothesis that UV radiation (UVR) could affect immune responses in mice infected with Borrelia burgdorferi. Immunity against the Lyme spirochete B. burgdorferi was studied in a murine model of UV-induced immune suppression. Borrelia-specific cellular and humoral responses were examined following immunosuppressive doses of UVR. Low-passage Borrelia were injected intradermally at the base of the tail following irradiation. At various time points after infection the blood was cultured for the presence of Borrelia and the serum analyzed for Borrelia-specific antibodies. Two weeks after infection one hind-limb joint was cultured for the presence of spirochetes and the contralateral joint was examined histologically for arthritis formation. The results demonstrated that UV irradiation, administered at the site of infection or at a distant site, suppressed Borrelia-specific cellular and humoral responses in infected mice. Suppression of delayed-type hypersensitivity and antibody responses to UV was abrogated by administration of anti-interleukin (IL)-10 after UV irradiation. In addition, UV irradiation altered the dissemination pattern of the bacteria from the skin into the blood and exacerbated arthritis when compared with unirradiated controls. From these studies we concluded that UV irradiation can modulate the immune response to Borrelia and exacerbate the subsequent arthritic component of Lyme disease in mice. Furthermore, our studies suggest that IL-10 is in part responsible for the suppression of both cellular and humoral responses in addition to playing a role in the development of Lyme arthritis.     

Interleukin‐17 Mediated Inflammatory Responses Are Required for Ultraviolet Radiation‐Induced Immune Suppression

Ultraviolet radiation (UVR) induces immunosuppression and is a major factor for development of skin cancer. Numerous efforts have been made to determine mechanisms for UVR‐induced immunosuppression and to develop strategies for prevention and treatment of UVR‐induced cancers. In the current study, we use IL‐17 receptor (IL‐17R) deficient mice to examine whether IL‐17 mediated responses have a role in UVB (290–320)‐induced immunosuppression of contact hypersensitivity responses. Results demonstrate that IL‐17 mediated responses are required for UVB‐induced immunosuppression of contact hypersensitivity responses. The systemic immune suppression and development of regulatory T cells are inhibited in UVB‐treated IL‐17R deficient mice compared to wild‐type animals. The deficiency in IL‐17R inhibits the infiltration and development of a tolerogenic myeloid cell population in UVB‐treated skin, which expresses CD11b and Gr‐1 and produces reactive oxygen species. We speculate that the development of the tolerogenic myeloid cells is dependent on IL‐17‐induced chemokines and inflammatory mediators in UVB‐treated skin. The inhibition of the tolerogenic myeloid cells may be attributed to the suppression of regulatory T cells in UVR‐treated IL‐17R^?/? mice. The findings may be exploited to new strategies for prevention and treatment of UVR‐induced skin diseases and cancers.