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

Nature Immunology volume 3, pages 859866 (2002) | Download Citation

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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 1 (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.

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Acknowledgements

We thank S. T. Ahmed and C. F. Nathan for critically reviewing the manuscript; J.-D. Ji and J.-L. Zhou for assistance with collecting murine macrophages; D. Levy for the type I IFNR–knockout mice; and J. Johnston for the sequences of SOCS1 primers. Supported by NIH grants AI46712 and AR46713 (to L. B. I.), a Cancer Research Institute Predoctoral Fellowship Training Grant (to X. H.), and NIH grants AI40987 and HL58695 (to A. E. K.). A. E. K. was also supported by the Veteran's Administration Research Service and the Gallagher Professorship for Arthritis Research.

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Affiliations

  1. Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.

    • Xiaoyu Hu
    •  & Lionel B. Ivashkiv
  2. Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA.

    • Carmen Herrero
    • , Wai-Ping Li
    • , Taras T. Antoniv
    •  & Lionel B. Ivashkiv
  3. Graduate Program in Molecular Biology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.

    • Erik Falck-Pedersen
  4. Veteran's Administration, Chicago Healthcare System, Lakeside Division, Northwestern University Medical School, Chicago, IL 60611, USA.

    • Alisa E. Koch
  5. Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.

    • Alisa E. Koch
    •  & James M. Woods
  6. Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.

    • G. Kenneth Haines III

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The authors declare no competing financial interests.

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Correspondence to Lionel B. Ivashkiv.

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DOI

https://doi.org/10.1038/ni828

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