Estrogen receptor signaling protects against immune suppression by UV radiation exposure

Abstract

The phytoestrogenic isoflavonoid equol is known to protect against solar-simulated UV radiation-induced inflammation, immunosuppression, and skin carcinogenesis. The mechanism may involve antioxidant actions, because equol not only is a radical scavenger but also enhances the induction of a relevant cutaneous antioxidant, metallothionein. However, this study in female hairless mice examined whether the estrogenicity of the isoflavonoid might be responsible. Protection by topically applied equol against photoimmune suppression was found to be strongly and dosedependently inhibited by the estrogen receptor (ER) antagonist ICI 182,780. Furthermore, ICI 182,780 alone was found to significantly exacerbate immunosuppression resulting from solar-simulated UV radiation irradiation, suggesting a natural role for the ER in photoimmune protection. In support of this role, topical application of the physiological ligand 17-␤-estradiol also provided dosedependent photoimmune protection, inhibitable by ICI 182,780, that was attributed largely to the inactivation of the downstream actions of cis-urocanic acid, an important endogenous immunosuppressive photoproduct. Thus, a hitherto unrecognized function of the ER as a normal photoprotective immune regulator in the skin was revealed. The relationship between equol and cutaneous metallothionein suggests an association of the ER with this inducible antioxidant in constraining the photoimmune-suppressed state and therefore in the prevention of the facilitation of photocarcinogenesis by this immunological defect. This role for the ER may underlie important gender-specific differences in UV-responsiveness that would reflect different needs for environmental photoprotection in males and females.cis-urocanic acid ͉ equol ͉ hairless mouse ͉ ICI 182,780 ͉ steroid hormone R ecent studies in mice with topically applied isoflavonoids derived from the red clover, Trifolium pratense, have shown that these phytochemicals may protect effectively against UV radiation-induced skin damage. Particular interest has centered on equol ([S]-4Ј7-dihydroxyisoflavane), an isoflavonoid metabolite produced from the dietary isoflavone daidzein by the gut microflora in mammals. Equol has been found to protect mice not only against UV radiation-induced cutaneous inflammation, observed as the sunburn reaction, but also against photoimmune suppression, which is evident as a defective contact hypersensitivity (CHS) reaction (1). Consistent with this observation, it was found that topical application to humans of an equol-related synthetic isoflavonoid, NV-07␣, also protected against the UV radiation-induced suppression of the elicited Mantoux reaction (2). In mice it was shown that the immunoprotective mechanism of topically applied equol involved inactivation of the downstream actions of cis-urocanic acid, a major UV-induced immunosuppressive photoproduct produced in the skin (1). Because chronic photoimmune suppression is a prerequisite for the promotion of UV radiation-initiated tumors (3), and because topica...

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