TNF-alpha suppresses IFN-gamma-induced MHC class II expression in HT1080 cells by destabilizing class II trans-activator mRNA

J Immunol. 1999 Aug 1;163(3):1435-40.

Abstract

Precise regulation of MHC class II gene expression is crucial for development and function of the immune system. Class II trans-activator (CIITA) has been shown to be required for constitutive and IFN-gamma-induced MHC class II transcription. TNF-alpha is commonly coexpressed with IFN-gamma during immune-mediated inflammatory responses and modulates IFN-gamma-stimulated MHC class II expression. The effect of TNF-alpha on MHC class II expression depends on cell type and cellular differentiation state. We show here that TNF-alpha suppresses IFN-gamma-induced CIITA mRNA accumulation, resulting in decreased MHC class II expression in human fibrosarcoma HT1080 cells. TNF-alpha also inhibits CIITA mRNA accumulation and protein expression in a tetracycline-regulated system without affecting promoter activity. CIITA mRNA, regulated by either IFN-gamma or tetracycline, was destabilized in the presence of TNF-alpha, suggesting that TNF-alpha utilizes a distinct mechanism to suppress MHC class II expression in HT1080 cells. Consistent with this interpretation, TNF-alpha blocked IFN-gamma-induced CIITA and MHC class II expression in mutant cells that are unresponsive to TGF-beta or IFN-beta. This is the first instance in which MHC class II expression is inhibited by destabilizing CIITA mRNA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Fibrosarcoma
  • Histocompatibility Antigens Class II / biosynthesis*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Immune Tolerance / genetics
  • Immunosuppressive Agents / pharmacology*
  • Interferon-gamma / antagonists & inhibitors*
  • Interferon-gamma / pharmacology*
  • Mutation / immunology
  • Nuclear Proteins*
  • RNA, Messenger / antagonists & inhibitors*
  • RNA, Messenger / metabolism
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology
  • Tetracycline / pharmacology
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Histocompatibility Antigens Class II
  • Immunosuppressive Agents
  • MHC class II transactivator protein
  • Nuclear Proteins
  • RNA, Messenger
  • Repressor Proteins
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • tetracycline resistance-encoding transposon repressor protein
  • Interferon-gamma
  • Tetracycline