Journal
NATURE IMMUNOLOGY
Volume 3, Issue 9, Pages 859-866Publisher
NATURE AMERICA INC
DOI: 10.1038/ni828
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Funding
- NHLBI NIH HHS [HL58695] Funding Source: Medline
- NIAID NIH HHS [AI46712, AI40987] Funding Source: Medline
- NIAMS NIH HHS [AR46713] Funding Source: Medline
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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-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.
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