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

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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Figure 1: Monocyte sensitization of IFN-γ signaling during PBMC cocultures.
Figure 2: Soluble factors produced in PBMC cocultures mediate IFN-γ signaling sensitization.
Figure 3: Monocyte IFN-γ signaling sensitization is mediated by IFN-γ, but not by IFN-α, in PBMC cocultures.
Figure 4: Subthreshold concentrations of exogenous IFN-γ can sensitize IFN-γ signaling in primary human monocytes and in macrophages from IFN-α/βR–deficient mice.
Figure 5: Priming with low doses of IFN-γ sensitizes activation of IFN-γ–inducible genes.
Figure 6: IFN-γ signaling sensitization mediated by increased STAT1 protein expression.
Figure 7: Regulation of IFN-γ signaling and STAT1 expression in vivo.

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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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Correspondence to Lionel B. Ivashkiv.

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Hu, X., Herrero, C., Li, WP. et al. Sensitization of IFN-γ Jak-STAT signaling during macrophage activation. Nat Immunol 3, 859–866 (2002). https://doi.org/10.1038/ni828

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