Regulation of Stimulated Cyclic AMP Synthesis by Urocanic Acid

ABSTRACT Urocanic acid (UCA) has been shown to mediate the UVB radiation‐induced immunosuppression initiated i’the skin by UV‐induced isomerization from the trans to the cis isomer. However, the mechanism by which cis. UCA acts is still unclear. Therefore, the present stud was undertaken to determine the effect of trans‐ and cis UCA on cyclic adenosine 3′,5′‐monophosphate (cAMP synthesis in human dermal fibroblasts, Golden Syria’hamster hepatocytes and in the human adenocarcinoms cell line, HT29. Neither trans‐ nor cis‐UCA was able is stimulate cAMP synthesis directly in any of the model: tested. In human dermal fibroblasts, cis‐UCA, in contras to trans‐UCA, specifically inhibited cAMP synthesis in duced by either prostaglandin (PG) El or PGE2 with s maximum inhibitory effect of 25‐30% at cis‐UCA con centrations greater than 1 μM and half‐maximum inhib itory effect (ECso) observed at 35 nM. The effect of cis‐UCA was not to stimulate phosphodiesterase and cAMP breakdown. The inhibitory effect of cis‐UCA (an imid azole derivative) was not mediated through stimulatiot of the α2‐adrenergic receptor. The inhibitory effect of cis UCA on stimulated cAMP synthesis was a function of the cell density and was only significant when the fibroblast were confluent or postconfluent. In contrast to the studie with human dermal fibroblasts, an inhibitory effect of cis‐UCA was not observed in either isolated hamster he patocytes or HT29 cells, in which cAMP synthesis wa stimulated by glucagon and vasoactive intestinal peptide respectively. These results point to a possible regulation of cAMP synthesis in fibroblasts as one mechanism by which cis‐UCA exerts its biological effect in the skin.