TGF-β mediated inhibition of class ii mhc expression occurs at the level of ciita

Academic Article

Abstract

  • The appropriate constitutive and inducible expression of class M major histocompatibility complex (MHC) antigens is essential for normal immune function, whereas aberrant expression in various tissues has been implicated in the pathogenesis of autoimmune diseases. Regulation of class II MHC genes occurs primarily at the level of transcription. Recently, a non-DNA binding protein, class II transactivator (CIITA), has been shown to be required for both constitutive and IFN-γ induced class II MHC expression. The immunosuppressive cytokine TGF-β inhibits IFN-γ induced class II expression in a variety of cell types, and this inhibition is mediated at the transcriptional level. In this study, we have examined the effect of TGF-β on class II expression in human astroglioma cell lines to determine how TGF-β exerts its inhibitory effect. The glioma cell line CRT does not constitutively express CIITA or class 11 MHC. CIITA mRNA is induced by IFN-γ in a time-dependent manner, with optimal expression detected 4 h after stimulation. IFN-γ induction of class II MHC mRNA is observed after 12 h of stimulation, with maximal expression after 24 h of exposure to IFN-γ. We demonstrate that both TGF-β and -to inhibit IFN-γ induced class II MHC mRNA and protein in the cell line CRT (-60-80% inhibition) as assessed by ribonuclease protection assay and fluorescence activated cell sorting, respectively. TGF-β and -βp also inhibit IFN-y induced expression of CIITA mRNA (-60-79% inhibition); inhibition of CIITA is more pronounced when cells are pretreated with TGF- for 12-24 h, then exposed to IFN-y. We are currently determining whether TGF-γ inhibits CIITA mRNA expression by destabilization of the CIITA message, or inhibition of transcription. These results indicate that TGF-β inhibits IFN-γ induction of CIITA mRNA expression and expression and/or activity of CIITA.
  • Published In

  • The FASEB Journal  Journal
  • Author List

  • Benveniste EN; Nquven V; Lee YJ
  • Volume

  • 10
  • Issue

  • 6