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.