Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases

Immunity. 2009 Oct 16;31(4):539-50. doi: 10.1016/j.immuni.2009.09.002.


Interferon-gamma (IFN-gamma) is an important mediator of immunity and inflammation that utilizes the JAK-STAT signaling pathway to activate the STAT1 transcription factor. Many functions of IFN-gamma have been ascribed to direct STAT1-mediated induction of immune effector genes, but recently it has become clear that key IFN-gamma functions are mediated by cross-regulation of cellular responses to other cytokines and inflammatory factors. Here, we review mechanisms by which IFN-gamma and STAT1 regulate signaling by Toll-like receptors, inflammatory factors, tissue-destructive cytokines, anti-inflammatory cytokines, and cytokines that activate opposing STATs. These signaling mechanisms reveal insights about how IFN-gamma regulates macrophage activation, inflammation, tissue remodeling, and helper and regulatory T cell differentiation and how Th1 and Th17 cell responses are integrated in autoimmune diseases.

Publication types

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

MeSH terms

  • Animals
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / metabolism
  • Cytokines / immunology
  • Cytokines / metabolism
  • Humans
  • Immunity, Active
  • Immunity, Innate
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Protein Kinases / immunology
  • Protein Kinases / metabolism
  • STAT Transcription Factors / immunology
  • STAT Transcription Factors / metabolism
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism


  • Cytokines
  • STAT Transcription Factors
  • Toll-Like Receptors
  • Interferon-gamma
  • Protein Kinases