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

Xiaoyu Hu, Carmen Herrero, Wai Ping Li, Taras T. Antoniv, Erik Falck-Pedersen, Alisa E. Koch, James M. Woods, G. Kenneth Haines, Lionel B. Ivashkiv

Research output: Contribution to journalArticlepeer-review

191 Scopus citations

Abstract

A general paradigm in signal transduction is ligand-induced feedback inhibition and the desensitization of signaling. We found that subthreshold concentrations of interferon-γ (IFN-γ), which did not activate macrophages, increased their sensitivity to subsequent IFN-γ stimulation; this resulted in increased signal transducer and activator of transcription I (STAT1) activation and increased IFN-γ-dependent gene activation. Sensitization of IFN-γ signaling was mediated by the induction of STAT1 expression by low doses of IFN-γ that did not effectively induce feedback inhibition. IFN-γ signaling was sensitized in vivo after IFN-γ 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-γ and regulates IFN-γ responses in acute and chronic inflammation.

Original languageEnglish
Pages (from-to)859-866
Number of pages8
JournalNature Immunology
Volume3
Issue number9
DOIs
StatePublished - Sep 2002
Externally publishedYes

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