Editors' ChoiceImmunology

Shedding Light on Immunosuppression

Science's STKE  21 Nov 2006:
Vol. 2006, Issue 362, pp. tw394
DOI: 10.1126/stke.3622006tw394

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-HT2A receptor with a Kd of 4.6 nM. Cis-UCA stimulated calcium mobilization in L-NCG-5-HT2A 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-HT2A 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-HT2A 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-HT2A receptor. Proc. Natl. Acad. Sci. U.S.A. 103, 17420-17425 (2006). [Abstract] [Full Text]