INHIBITION OF IFN-GAMMA INDUCTION OF CLASS-II MHC GENES BY CAMP AND PROSTAGLANDINS

Triggering of the cyclic AMP (cAMP) signal transduction pathway inhibits the interferon gamma (IFN-gamma) -mediated induction of class II major histocompatibility (MHC) genes. We have investigated the mechanism of the inhibition of IFN-gamma induction of the murine Au. class II MHC gene by cAMP and E series prostaglandins (PGEs). 151 base pairs of the Au promoter were sufficient to confer positive regulation by IFN-gamma and negative regulation by cAMP which accurately mirrored the regulation of the endogenous A alpha gene, cAMP also inhibited the IFN-gamma activation of the Fc gamma receptor I (Fc gamma RI) gene promoter, an ''early'' promoter which is activated immediately after treatment of cells with IFN-gamma. PGEs, which cause an elevation in intracellular cAMP, inhibited the induction of the A alpha promoter, and inhibition was greater in the presence of tumor necrosis factor alpha (TNF alpha). A mutational analysis of the Act promoter showed that all four conserved class II promoter elements, the S, X1, X2, and Y boxes, play a role in mediating A alpha promoter activation by IFN-gamma. Mutations in these elements did not diminish the cAMP inhibition of promoter activation by IFN-gamma. Thus, conserved class II promoter sequences which mediate most known examples of positive and negative regulation, including cAMP inhibition of constitutive class II expression, do not mediate cAMP inhibition of IFN-gamma activation of the A alpha promoter. We suggest that this inhibition may be mediated by a novel class II promoter element or by disruption of an early step in the IFN-gamma signal transduction pathway.