Class II MHC antigens are normally absent in cells from the central nervous system (CNS), but can be induced by stimulation with IFN-γ. The transcriptional activation of class II MHC genes requires the induction of the class II transactivator (CIITA). IL-1β has been shown to inhibit IFN-γ induced class II MHC expression in astrocytes. We investigated the underlying mechanism of this inhibitory effect of IL-1β. Our findings demonstrate that IL-1β prevents the transcriptional activation of HLA-DRA upon treatment with IFN-γ. Furthermore, we demonstrate that IFN-γ induction of CIITA mRNA expression is greatly reduced by pretreating cells with IL-1β. Using human CIITA type IV promoter constructs linked to luciferase, we determined that IFN-γ induced CIITA transcription is also inhibited by IL-1β treatment, indicating that IL-1β mediated inhibition of CITTA is due to repression of CIITA transcription. IL-1β did not interfere with IFN-γ receptor signal transaction, since tyrosine phosphorylation, nuclear translocation and DNA binding of STAT-1α was not affected by IL-1β. Thus, the inhibitory mechanism of IL-1β appears to be independent of STAT-1α. The inhibitory effect of IL-1β was specific for IFN-γ induced class IIMHC expression, since both cytokines (IL-1β, IFN-γ) synergistically enhanced ICAM-1 expression on astrocytes. This study suggests that IL-1β may play a role in limiting immunoreactivity in the CNS by reducing class II MHC induction.