Class II MHC Ags are critical for the initiation of immune responses by presenting Ag to T lymphocytes, leading to their activation and differentiation. The transcriptional activation of class II MHC genes requires the induction of the class II transactivator (CIITA) protein, a master regulator that is essential for both constitutive and IFN-γ-inducible class II MHC expression. The cytokine IL-1β has been shown to inhibit IFN- γ-induced class II MHC expression in various cell types. We investigated the underlying mechanism of this inhibitory effect of IL-1β using human astroglioma cell lines. Our findings demonstrate that IL-1β prevents the expression of class II MHC mRNA and protein upon treatment with IFN-γ. Furthermore, we demonstrate that IFN-γ induction of CIITA mRNA expression is inhibited by treatment of cells with IL-1β. IL-1β suppressed IFN-γ activation of the type IV CIITA promoter in astroglioma cells, indicating that the inhibitory influence of IL-1β is mediated by inhibition of CIITA transcription. IL-1β did not interfere with IFN-γ receptor signal transduction, since tyrosine phosphorylation, nuclear translocation, and DNA binding of STAT-1α to an IFN-γ activation sequence of the type IV CIITA promoter were not affected by IL-1β. As well, IL-1β treatment did not affect the ability of IFN-γ-induced interferon-regulatory factor-1 (IRF-1) to bind the IRF-1 element within the type IV CIITA promoter. This study suggests that IL-1β may play a role in regulating immunoreactivity by inhibiting transcription of the CIITA gene, thereby reducing subsequent class II MHC expression.