IL-1β Inhibits IFN-γ-Induced Class II MHC Expression by Suppressing Transcription of the Class II Transactivator Gene

Abstract

AbstractClass 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.