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Amplification of IFN-α-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors

Nature Immunology volume 5, pages 1181–1189 (2004)Cite this article

Abstract

A key function of interferons is priming multiple cell types for enhanced activation by cytokines and inflammatory factors, including tumor necrosis factor, bacterial lipopolysaccharide and interferons themselves. Here we show that interferon-α (IFN-α)–induced activation of the transcriptional activator STAT1 and inflammatory STAT1 target genes was enhanced in IFN-γ-primed macrophages. Enhanced IFN-α signaling and proinflammatory function were dependent on the tyrosine kinase Syk and on adaptor proteins that activate Syk through immunoreceptor tyrosine activation motifs. Increased STAT1 expression contributed to enhanced IFN-α-induced STAT1 activation in primed macrophages. These results identify a mechanism by which crosstalk between cytokine and immune cell–specific immunoreceptor tyrosine activation motif–dependent signaling pathways regulates macrophage responses to IFN-α.

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Figure 1: IFN-γ priming of macrophages increases IFN-α-induced STAT1 activation.
Figure 2: IFN-γ priming enhances IFN-α-induced chemokine expression and cell migration.
Figure 3: IFN-γ priming does not affect proximal IFN-α signaling.
Figure 4: Syk mediates increased phosphorylation of STAT1 and increased production of chemokines in IFN-γ primed macrophages.
Figure 5: Syk phosphorylation of STAT1 and FcRγ-DAP12 dependence of priming.
Figure 6: Increased STAT1 expression potentiates the priming effect of Syk.
Figure 7: Model for enhanced IFN-α STAT1 activation mediated by Syk, increased STAT1 expression and FcRγ and DAP12 adaptor proteins.

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Acknowledgements

We thank V. Tybulewicz, M. Muller, G. Yap, C. Schindler and L. van Parijs for providing mice, bone marrow cells and plasmids; X. Ma and K. Park-Min for critically reviewing the manuscript; and M. Humphrey and M. Nakamura for discussions. Supported by the National Institutes of Health (L.B.I.), Abbott Scholar Program (I.T.) and Cancer Research Institute (X.H.).

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Authors and Affiliations

  1. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, 10021, New York, USA

    Ioannis Tassiulas, Xiaoyu Hu, Hao Ho, Yogita Kashyap, Paul Paik & Lionel B Ivashkiv

  2. Department of Medicine, Hospital for Special Surgery, New York, 10021, New York, USA

    Ioannis Tassiulas & Lionel B Ivashkiv

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

    Xiaoyu Hu & Lionel B Ivashkiv

  4. Department of Laboratory Medicine, University of California, San Francisco, 94143, California, USA

    Yongmei Hu & Clifford A Lowell

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Correspondence to Lionel B Ivashkiv.

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Tassiulas, I., Hu, X., Ho, H. et al. Amplification of IFN-α-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nat Immunol 5, 1181–1189 (2004). https://doi.org/10.1038/ni1126

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