Decrease in langerhans cells and increase in lymph node dendritic cells following chronic exposure of mice to suberythemal doses of solar simulated radiation

Exposure of certain strains of mice to ultraviolet radiation (UVR) causes suppression of some innate and adaptive immune responses. One such consequence of acute UVB exposure is a reduction in the number of Langerhans cells (LC) in the epidermis and an increase in dendritic cells (DC) in lymph nodes draining the irradiated skin sites. Exposure to chronic UVB irradiation also has effects on the immune system, but it is unknown what effects are caused by repeated doses of solar simulated radiation (SSR). Consequently, the main aims of the present study were to determine whether repeated exposure to low doses of SSR would lead to similar changes in these cell populations and whether chronic doses of SSR activate a protective photoadaptation mechanism. Groups of C3H/HeN mice were irradiated daily with 3.7 J/cm(2) SSR from Cleo Natural lamps for 2, 10, 20, 30 or 60 days. Further groups of mice received an additional dose of 7.4 J/cm(2) SSR on days 2, 10, 30 or 60 to test for photoadaptation. The numbers of LC in the epidermis and DC in the lymph nodes draining irradiated skin sites were counted 24 h after the final irradiation. With the exception of mice irradiated for only 2 days, LC were significantly reduced throughout the chronic irradiation protocol, and no recovery occurred. DC numbers were significantly increased in the draining lymph nodes of mice irradiated for 20 days and 60 days.     

Ultraviolet B but not A radiation activates suppressor B cells in draining lymph nodes

Immunosuppressive doses of solar-simulated UV radiation activate lymph node B cells that can suppress primary immunity by inhibiting the function of dendritic cells. The aim of this study was to determine the waveband responsible for activation of these suppressor B cells. We exposed C57BL/6 mice to various doses of either UVA or UVB radiation and analyzed the number and activation state of lymph node antigen-presenting cells (APC). Immunosuppressive doses of UVB but not UVA activated B cells as assessed by major histocompatibility complex II (MHC II) expression and doubled their numbers in draining lymph nodes. Higher doses of UVA that were not immunosuppressive actually suppressed B cell activation. Our results show that UVA and UVB suppress systemic immunity via different mechanisms. Lymph node B cells are activated in response to immunosuppressive doses of UVB but not UVA. Thus, the activation state of lymph node APC appears to be important for UV immunomodulation.     

Cell Cycle Effects and Concomitant p53 Expression in Hairless Murine Skin after Longwave UVA (365 nm) Irradiation: A Comparison with UVB Irradiation

Abstract— Ultraviolet A (UVA,315–400 nm) radiation is known to be a complete carcinogen, but in contrast to UVB (280-315 nm) radiation, much of the cell damage is oxygen dependent (mediated through reactive oxygen species), and the dominant premutational DNA lesion(s) remains to be identified. To investigate further the basic differences in UVA and UVB carcinogenesis, we compared in vivo cellular responses, viz. cell cycle progression and transient p53 expression in the epidermis, after UVA1 (340-400 nm) exposure with those after broadband UVB exposure of hairless mice. Using flow cytometry we found a temporary suppression of bromodeoxyuridine (BrdU) uptake in S-phase cells both after UVB and UVA1 irradiation, which only in the case of UVB is followed by an increase to well over control levels. With equally erythemogenic doses (1-2 MED), the modulation of BrdU uptake was more profound after UVB than after UVA1 irradiation. Also, a marked transient increase in the percentage of S-phase cells occurred both after UVB and after UVA1 irradiation, but this increase evolved more rapidly after UVA1 irradiation. Further, p53 expression increased both after UVB and UVA1 irradiations, with peak expression already occurring from 12 to 24 h after UVA1 exposure and around 24 h after UVB exposure. Overall, UVA1 radiation appears to have less of an impact on the cell cycle than UVB radiation, as measured by the magnitude and duration of changes in DNA synthesis and cells in S phase. These differences are likely to reflect basic differences between UVB and UVA1 in genotoxicity and carcinogenic action.     

Effects of ultraviolet-A exposure on ultraviolet-B-induced accumulation of specific flavonoids in Brassica napus.

Many plant species are able to acclimate to changes in ultraviolet-B radiation (UVB) (290-320 nm) exposure. Due to the wide range of targets of UVB, plants have evolved diverse repair and protection mechanisms. These include increased biosynthesis of UVB screening compounds, elevated antioxidant activity and increased rates of DNA repair. We have shown previously that Brassica napus L. cv Topas plants can acclimate quite effectively to environmentally relevant increases in UVB through the accumulation of specific flavonoids in the leaf epidermis. However, B. napus was found to lose other flavonoids when plants are exposed to ultraviolet-A radiation (UVA) (320-400 nm) and/or UVB (Wilson et al. [1998] Photochem. Photobiol. 67, 547-553). In this study we demonstrate that the levels of all the extractable flavonoids in the leaves of B. napus plants are decreased in a dose-dependent manner in response to UVA exposure. Additionally, the accumulation of the extractable flavonoids was examined following a shift from photosynthetically active radiation (PAR) + UVA to PAR + UVB to assess if preexposure to UVA affected UVB-induced flavonoid accumulation. UVA preexposures were found to impede UVB-induced accumulation of some flavonoids. This down regulation was particularly evident for quercetin-3-O-sophoroside and quercetin-3-O-sophoroside-7-O-glucoside, which is interesting because quercetins have been demonstrated to be induced by UVB and correlated with UVB tolerance in some plant species. The photobiological nature of these UVA-mediated effects on flavonoid accumulation implies complex interactions between UVA and UVB responses.     

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.     

Chronic Low-Dose UVA Irradiation Induces Local Suppression of Contact Hypersensitivity, Langerhans Cell Depletion and Suppressor Cell Activation in C3H/HeJ Mice

Abstract— It has previously been demonstrated that chronic low-dose solar-simulated UV radiation could induce both local and systemic immunosuppression as well as tolerance to a topically applied hapten. In this study, we have used a chronic low-dose UV-irradiation protocol to investigate the effects of UVA on the skin immune system of C3H/HeJ mice. Irradiation with UVA+B significantly suppressed the local and systemic primary contact hypersensitivity (CHS) response to the hapten 2,4,6-trinitrochlo-robenzene. Furthermore UVA+B reduced Langerhans cell (LC) and dendritic epidermal T cell (DETC) densities in chronically UV-irradiated mice. Ultraviolet A irradiation induced local, but not systemic, immunosuppression and reduced LC (32%) but not DETC from the epidermis compared to the shaved control animals. Treatment of mice with both UVA+B and UVA radiation also induced an impaired secondary CHS response, and this tolerance was transferable with spleen cells. These results suggest that depletion of LC, but not DETC, may be involved in UVA-induced local immunosuppression in our model, and that tolerance was induced in the presence of normal numbers of DETC. Hence exposure of C3H/HeJ mice 5 days per week for 4 weeks with UVA can induce local immunosuppression and tolerance.     

UVA II Exposure of Human Skin Results in Decreased Immunization Capacity, Increased Induction of Tolerance and a Unique Pattern of Epidermal Antigen-Presenting Cell Alteration

Abstract— The risks incurred from increased exposure to UVA II (320-340 nm) (i.e. during sunscreen use and extended outdoor exposure, tanning parlors) are not well understood. Therefore, we explored the effects of UVA II on skin immune responses in humans. After a single local exposure (4 minimum erythemal dose [MED]) using a xenon arc lamp filtered with a narrow bandpass filter (335 ± 5 nm full width at half maximum), individuals were contact-sensitized with dinitrochlorobenzene (DNCB) through a UVA II exposure site or through normal skin. UVA II induced a marked decrease in the magnitude of skin immune responses (P < 0.0001). The UVA II group had only 29% successful sensitizations, as compared to 83% in the control group. The percentage of individuals who remained tolerant to DNCB after two sensitizations was 23.6% for the UVA II-exposed group, as compared to 3.8% in the controls (P= 0.006). UVA II also uniquely altered the type of antigen-presenting cells present in the epidermis. Human leukocyte antigen (HLA)-DR+ cells in control epidermal cell suspensions (C-EC) comprised a single, homogeneous population of Langerhans cells (LC) with the phenotype: CD1a^hi DR^mid CD11b^? CD36^? (1.5 ± 0.3% of EC). UVA II irradiation reduced the number of such LC to 0.6 ± 0.2% of EC. Although cells expressing the macrophage phenotype: CD1a DR^hi CD11b+ CD36+ were increased in UVA II skin, relative to C-EC, these comprised only 10.1 ± 6.1% of the DR+ cells, which is less than that after UVB exposure. Also distinct from UVB, a third population was found in UVA II-EC, which exhibited a novel phenotype: CD1a+ DR+ CD36+ CDllb+; these comprised 11.1 ± 6.9% of the DR+ UVA II-EC. In conclusion, despite the above differences in infiltrating DR cells, both UVB and UVA II reduce the skin's ability to support contact sensitization, induce active suppression (tolerance) and induce a reduction in LC.     

THE EFFECT OF CHRONIC LOW-DOSE UVB RADIATION ON LANGERHANS CELLS, SUNBURN CELLS, UROCANIC ACID ISOMERS, CONTACT HYPERSENSITIVITY and SERUM IMMUNOGLOBULINS IN MICE

Abstract— C3H mice were irradiated three times a week for up to 6 weeks with either 500 J/m² or 1000 J/m² broadband UVB (270–350 nm) or 3000 J/m² narrowband UVB (311–312 nm; TL01 source). Each dose was suberythemal to the mouse strain used. The number of Langerhans cells (LC) in the epidermis was reduced by over 50% after 2 weeks of irradiation with the UVB source and by 20% following TL01 irradiation. Continued irradiation for up to 6 weeks resulted in no further decrease in LC numbers in the case of the UVB source but a steady decline to 40% in the case of the TL01 source. Sunburn cells were detected following irradiation with both sources but the numbers were very low in comparison with acute exposure. Ultraviolet-B exposure resulted in doubling of the thickness of the epidermis throughout the 6 weeks of irradiation while TL01 exposure did not alter epidermal thickness. Conversion of trans- to ew-urocanic acid (UCA) was observed with both UVB and TL01 sources. The percentage of cis -UCA started to return to normal after 4 weeks of TL01 exposure despite continued irradiation. As observed following a single exposure, the contact hypersensitivity (CH) response was significantly reduced following 6 weeks of UVB irradiation but was unaffected by TL01 exposure, indicating no correlation between cis -UCA levels and CH response. Total serum immunoglobulin levels remained unchanged throughout the 6 weeks of UVB or TL01 irradiation but IgE titers significantly increased in all cases in the first 2 weeks of irradiation, indicating a possible shift to a T_H2 cytokine profile. The IgE levels started to return to normal at later times. Thus chronic broadband UVB exposure induces a number of cutaneous and systemic responses that are likely to be dose dependent, while chronic TL0I exposure induces only some of the these responses.     

No adaptation to UV-induced immunosuppression and DNA damage following exposure of mice to chronic UV-exposure

It is well known that ultraviolet (UV) radiation induces erythema, immunosuppression and carcinogenesis. We hypothesized that chronic exposure to solar UV radiation induces adaptation that eventually prevents the suppression of acquired immunity. We studied adaptation for UV-induced immunosuppression after chronic exposure of mice to a suberythemal dose of solar simulated radiation (SSR) with Cleo Natural lamps, and subsequent exposure to an immunosuppressive dose of solar or UVB radiation (TL12). After UV dosing, the mice were sensitized and challenged with either diphenylcyclopropenone (DPCP) or picryl chloride (PCl). To assess the adaptation induced by solar simulated radiation, we measured the proliferative response and cytokine production of skin-draining lymph node cells after immunization to DPCP, the contact hypersensitivity (CHS) response to PCl, and thymine-thymine (T-T) cyclobutane dimers in the skin of mice. After induction of immunosuppression by SSR or by TL12 lamps, the proliferative response of draining lymph node cells after challenge with DPCP, or the CHS after challenge with PCl, showed significant suppression of the immune response. Chronic irradiation from SSR preceding the immunosuppressive dose of UV failed to restore the suppressed immune response. Reduced lipopolysaccharide-triggered cytokine production (of IL-12p40, IFN-gamma, IL-6 and TNF-alpha) by draining lymph node cells of mice sensitized and challenged with DPCP indicated that no adaptation is induced. In addition, the mice were not protected from T-T dimer DNA damage after chronic solar irradiation. Our studies reveal no evidence that chronic exposure to low doses of SSR induces adaptation to UV-induced suppression of acquired immunity.     

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.     

Attenuation of DNA damage in the dermis and epidermis of the albino hairless mouse by chronic exposure to ultraviolet-A and -B radiation

Mammalian skin is vulnerable to the photocarcinogenic and photoaging effects of solar UV radiation and defends itself using a variety of photoprotective responses including epidermal thickening, tanning and the induction of repair and antiradical systems. We treated Skh-1 albino hairless mice for 60 days with ultraviolet-A (UVA) or ultraviolet-B (UVB) radiation and measured the frequency of cyclobutane pyrimidine dimers and pyrimidine(6-4)pyrimidone photoproducts induced by a single acute sunburn dose of UVB at different stages of the chronic treatment. We found that both UVA and UVB exposure produced a photoprotective response in the dermis and epidermis and that the degree of photoproduct attenuation was dependent on dose, wavelength and the type of damage induced. Although epidermal thickening was important, our data suggest that UV protective compounds other than melanin may be involved in mitigating the damaging effects of sunlight in the skin.     

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.     

Furocoumarin-induced Epidermal Melanogenesis Does Not Protect Against Skin Photocarcinogenesis in Hairless Mice

Topical 6,4,4'-trimethylangelicin (TMA) plus UVA was used to induce intense epidermal pigmentation in inbred HRA.HRII-c/+/Skh hairless pigmented mice over a 13 day period. Subsequent UVB/UVA exposure was used to assess the photoprotective properties of this tan using skin tumors as an endpoint. Comparisons were always made with sibling albino mice. The TMA/UVA treatment was shown to be not carcinogenic when treated mice were compared with untreated control mice over 25 weeks. The tan faded despite daily exposure to UVB/UVA and did not afford any protection when TMA/UVA-treated mice with subsequent UVB/UVA were compared with pigmented mice treated with UVB/UVA only. In one group, the TMA-induced tan was maintained by application of TMA three times a week prior to UVB/UVA for the duration of the experiment. This treatment was associated with a significant increase in tumor risk in both pigmented and albino mice compared to groups treated with UVB/UVA alone. Although pigmented mice had a significant photoprotective advantage, it was shown to be outweighed by the carcinogenic risks of the TMA maintenance treatment when they were compared with mice that did not have this treatment. Nonpretanned pigmented mice developed mild pigmentation during UVB/UVA treatment that was shown to have no protective effect when those mice were compared with albinos. We conclude that induced epidermal tanning with or without furocoumarin enhancement is not an effective way to prevent skin cancer in the HRA.HRII-c/+/Skh mouse model.     

COMPARATIVE EFFECT OF UVA AND UVB ON CULTURED RABBIT LENS

Abstract Effects on lens physiology of UVB and UVA used separately and sequentially were investigated using 4 week old rabbit lenses in organ culture. Narrowband UVB at 0.3 J/cm²= joules/lens (1 h exposure) has little effect on sodium and calcium concentrations in the lens interior or transparency of lenses subsequently cultured for 20 h after a 1 h exposure. With an incident energy of 3 J/cm² of broadband UVB (295–330 nm), lenses become opaque and slightly swollen with significant ion imbalances during culture over a 1 day period. In contrast, lenses exposed to approximately 6–24 J/cm² of UVA (330–400 nm) remain transparent after 1 day of culture. Extended culture up to 4 days reveals no signs of opacification. Ion homeostasis and normal lens hydration are also maintained in UVA-irradiated lenses. The presence of 95% oxygen during UVA irradiation is also without effect. Broadband UVA irradiation is damaging, however, if lenses are first exposed to subthreshold doses of narrowband UVB (307 ± 5 nm) irradiation, viz . 0.3 J/cm². Thus, sequential UVB/UVA irradiation at subthreshold doses causes impaired active cation transport and accumulation of sodium and calcium accompanying lens opacification.     

The Effect of Chronic Treatment of Mice with Urocanic Acid Isomers

Abstract— Trans-urocanic acid (trans-UCA) accumulates in the upper layers of the epidermis and can be isomerized to cis-UCA by UV light irradiation. Cis-urocanic acid possesses immunosuppressive properties that have led to its consideration as one of the initiators of UV-induced immunosuppression. High quantities of cis-UCA persist in human skin for prolonged periods in the summer months. In the present study, mice were injected intradermaUy with trans-UCA and cis-UCA three times a week for 4 weeks in order to ascertain the long-term effects of the presence of these compounds in the skin. The weight of mice and of their spleens were unaffected by the cis- or trans-UCA treatment. A decrease in thymus weight, accompanied by an increase in lymph node weight, was detected in the cis-UCA-treated mice compared with trans-UCA-treated mice and untreated controls. A net accumulation of lymphocytes and dendritic cells (DC) in lymph nodes was evident following cis-UCA treatment but the percentage of both CD4+and CD8+lymphocytes as well as Ia+DC remained constant among the different treatment groups, indicating that there was no specific migration or proliferation of a particular subset of cells. The in vitro lymphoproliferative response of lymph node cells to the mitogen concanavalin A was significantly sup pressed by cis-UCA treatment. The density of Langerhans cells in the epidermis of the ears was not altered by the chronic cis-UCA treatment. However, chronic cis-UCA treatment did suppress the mixed skin lymphocyte reaction response utilizing epidermal cells from the ears (an uninjected area of skin), indicating a systemic suppression. Compared with trans-UCA treatment, chronic cis-UCA treatment did not cause a significant reduction in the contact hypersensitivity response to oxazolone or the delayed hypersensitivity response to herpes simplex virus. Thus, chronic treatment with cis-UCA led to the suppression of some, but not all, of the immune parameters that are affected by UVB irradiation.     

The induction of immunity to a protein antigen using an adjuvant is significantly compromised by ultraviolet A radiation

Ultraviolet (UV) radiation from sunlight causes skin cancer and inhibits priming of the immune system during vaccination. However the dose related effects of the different components of sunlight (UVA and UVB) are complex and require further investigation. Using ovalbumin as a model protein vaccine with saponin as adjuvant we show that both UVA and UVB can suppress the DTH response to a poorly immunogenic protein. Increasing doses of UVB induced increased levels of immunosuppression and tolerance. UVA however, caused a bi-phasic dose response with intermediate but not low or high doses causing primary immunosuppression. No dose of UVA caused significant tolerance. Similar results were observed in both C57BL/6 and Balb/c mice. Our data confirms the complex immunomodulatory dose effects of UVA and UVB for a protein antigen, and shows that both UVB and UVA can suppress immunity induced by a protein with adjuvant. This highlights the importance of considering sun exposure patterns in the future success of both preventing skin cancer development and enhancing vaccination regimes.     

LACK OF CORRELATION BETWEEN SUPPRESSION OF CONTACT HYPERSENSITIVITY BY UV RADIATION AND PHOTOISOMERIZATION OF EPIDERMAL UROCANIC ACID IN THE HAIRLESS MOUSE

Abstract The immunological consequences of exposure to UVA (320–400 nm) radiation are unclear. This study describes the relationship between the generation of epidermal cis -urocanic acid and the ability to respond to a contact-sensitizing agent, in hairless mice exposed to different UV radiation sources, which incorporate successively greater short-wavelength cutoff by filtration of the radiation from fluorescent UV tubes. Mice were exposed to these radiation sources at doses systematically varying in UVB radiation content but supplying increasing proportions of UVA radiation. All radiation sources were found to generate approximately 35% cis -urocanic acid in the epidermis, thus normalizing the sources for cis -urocanic acid production. However, only those sources richest in short-wavelength UVB resulted in suppression of the systemic contact hypersensitivity response. These sources also induced the greatest erythema reaction, measured as its edema component, in the exposed skin. A strong correlation was thus demonstrated between the induction of edema and the suppression of contact hypersensitivity, but there appeared to be no correlation between the generation of epidermal cis-urocanic acid and suppression of contact hypersensitivity. The sources richest in UVA content did not result in suppression of contact hypersensitivity: furthermore mice previously irradiated with such UVA-rich sources were refractory to the immunosuppressive action of exogenous cis-urocanic acid. A protective effect of the increased UVA content thus appeared to be inhibiting immunosuppression by the available endogenously generated or exogenously applied cⁱs-urocanic acid.     

Endogenous Retinoic Acid Required to Maintain the Epidermis Following Ultraviolet Light Exposure in SKH‐1 Hairless Mice

Ultraviolet light B (UVB) exposure induces cutaneous squamous cell carcinoma (cSCC), one of the most prevalent human cancers. Reoccurrence of cSCC in high‐risk patients is prevented by oral retinoids. But oral retinoid treatment causes significant side effects; and patients develop retinoid resistance. Exactly how retinoids prevent UVB‐induced cSCC is currently not well understood. Retinoid resistance blocks mechanistic studies in the leading mouse model of cSCC, the UVB‐exposed SKH‐1 hairless mouse. To begin to understand the role of retinoids in UVB‐induced cSCC we first examined the localization pattern of key retinoid metabolism proteins by immunohistochemistry 48 h after UVB treatment of female SKH‐1 mice. We next inhibited retinoic acid (RA) synthesis immediately after UVB exposure. Acute UVB increased RA synthesis, signaling and degradation proteins in the stratum granulosum. Some of these proteins changed their localization; while other proteins just increased in intensity. In contrast, acute UVB reduced the retinoid storage protein lectin:retinol acyltransferase (LRAT) in the epidermis. Inhibiting RA synthesis disrupted the epidermis and impaired differentiation. These data suggest that repair of the epidermis after acute UVB exposure requires endogenous RA synthesis.