Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation

Nat Immunol. 2002 Sep;3(9):859-66. doi: 10.1038/ni828. Epub 2002 Aug 12.


A general paradigm in signal transduction is ligand-induced feedback inhibition and the desensitization of signaling. We found that subthreshold concentrations of interferon-gamma (IFN-gamma), which did not activate macrophages, increased their sensitivity to subsequent IFN-gamma stimulation; this resulted in increased signal transducer and activator of transcription 1 (STAT1) activation and increased IFN-gamma#150;dependent gene activation. Sensitization of IFN-gamma signaling was mediated by the induction of STAT1 expression by low doses of IFN-gamma that did not effectively induce feedback inhibition. IFN-gamma signaling was sensitized in vivo after IFN-gamma injection, and STAT1 expression was increased after injection of lipopolysaccharide and in rheumatoid arthritis synovial cells. These results identify a mechanism that sensitizes macrophages to low concentrations of IFN-gamma and regulates IFN-gamma responses in acute and chronic inflammation.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / biosynthesis
  • Cells, Cultured
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation
  • Humans
  • Interferon-gamma / physiology*
  • Intracellular Signaling Peptides and Proteins*
  • Janus Kinase 1
  • Janus Kinase 2
  • Macrophage Activation / physiology*
  • Protein-Tyrosine Kinases / physiology*
  • Proto-Oncogene Proteins*
  • Repressor Proteins*
  • STAT1 Transcription Factor
  • Signal Transduction*
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / physiology*
  • Transcriptional Activation


  • Carrier Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • SOCS1 protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2