Immunology Shedding Light on Immunosuppression

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

Ultraviolet (UV) radiation from sunlight has been implicated in causing skin cancer and, perhaps not coincidentally, suppresses the immune response. UV-dependent immune suppression depends on the absorption of its electromagnetic energy by an epidermal photoreceptor. Trans-urocanic acid (UCA) isomerizes to cis-UCA in response to UV exposure, and epidermal UCA has long been known to act as a UV photoreceptor that can mediate immune suppression. The mechanism whereby cis-UCA affects the immune response, however, has been unclear. Cis-UCA forms a ringlike structure in solution, and Walterscheid et al.--who serendipitously observed that the serotonin [5-hydroxytryptamine (5-HT)] receptor antagonist ketanserin blocked UV- and cis-UCA-mediated immune suppression--used competitive binding assays to show that radiolabeled cis-UCA bound to human serotonin receptors. Immunoprecipitation analysis with antibodies directed against cis-UCA or serotonin confirmed the structural similarity of the two compounds, and saturation binding studies indicated that cis-UCA bound to the human 5-HT_2A receptor with a K_d of 4.6 nM. Cis-UCA stimulated calcium mobilization in L-NCG-5-HT_2A cells but not in untransfected controls [LM(TK^–) cells], and this calcium mobilization was blocked by ketanserin. UV- or cis-UCA-induced immune suppression in mice was blocked by antibodies directed against serotonin (as well as by antibodies directed against cis-UCA) and by 5-HT_2A receptor antagonists. Thus, the authors propose that the ability of cis-UCA to suppress the immune response--and that of UV radiation--is mediated through the 5-HT_2A receptor.

J. P. Walterscheid, D. X. Nghiem, N. Kazimi, L. K. Nutt, D. J. McConkey, M. Norval, S. E. Ullrich, Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT_2A receptor. Proc. Natl. Acad. Sci. U.S.A. 103, 17420-17425 (2006). [Abstract] [Full Text]