IL-1 beta inhibits IFN-gamma-induced class II MHC expression by suppressing transcription of the class II transactivator gene

Class II MHC Ags are critical for the initiation of immune responses by pre senting Ag to T lymphocytes, leading to their activation and differentiatio n. The transcriptional activation of class II MHC genes requires the induct ion of the class II transactivator (CIITA) protein, a master regulator that is essential for both constitutive and IFN-gamma-inducible class II MHC ex pression. The cytokine IL-1 beta has been shown to inhibit IFN-gamma-induce d class II MHC expression in various cell types. We investigated the underl ying mechanism of this inhibitory effect of IL-1 beta using human astroglio ma cell lines, Our findings demonstrate that IL-1 beta prevents the express ion of class II MHC mRNA and protein upon treatment with IFN-gamma, Further more, we demonstrate that IFN-gamma induction of CIITA mRNA expression is i nhibited by treatment of cells with IL-1 beta. IL-1 beta suppressed IFN-gam ma activation of the type IV CIITA promoter in astroglioma cells, indicatin g that the inhibitory influence of IL-1 beta is mediated by inhibition of C IITA transcription. IL-1 beta did not interfere with IFN-gamma receptor sig nal transduction, since tyrosine phosphorylation, nuclear translocation, an d DNA binding of STAT-1 alpha to an IFN-gamma activation sequence of the ty pe IV CIITA promoter were not affected by IL-1 beta, As well, IL-1 beta tre atment did not affect the ability of IFN-gamma-induced interferon-regulator y factor-1 (IRF-1) to bind the IRF-1 element within the type IV CIITA promo ter, This study suggests that IL-1 beta may play a role in regulating immun oreactivity by inhibiting transcription of the CIITA gene, thereby reducing subsequent class II MHC expression.