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Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1

Nature Immunology volume 9, pages 542–550 (2008)Cite this article

A Corrigendum to this article was published on 15 February 2011

This article has been updated

Abstract

Unbalanced production of proinflammatory cytokines and type I interferons in immune responses may lead to immunopathology; thus, the mechanisms that ensure the beneficial production of proinflammatory cytokines and type I interferons are of particular importance. Here we demonstrate that the phosphatase SHP-1 negatively regulated Toll-like receptor–mediated production of proinflammatory cytokines by inhibiting activation of the transcription factor NF-κB and mitogen-activated protein kinase. Simultaneously, SHP-1 increased the production of type I interferon mediated by Toll-like receptors and the helicase RIG-I by directly binding to and inhibiting activation of the kinase IRAK1. Our data demonstrate that SHP-1 contributes to immune homeostasis by balancing the production of proinflammatory cytokines and type I interferons in the innate immune response.

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Figure 1: SHP-1 inhibits the production of proinflammatory cytokines but increases IFN-β production in TLR3- and TLR4-activated splenocytes.
Figure 2: SHP-1 inhibits TNF production but increases IFN-β production in TLR3- and TLR4-activated DCs and macrophages.
Figure 3: SHP-1 increases TLR-mediated expression of type I interferon after viral infection.
Figure 4: SHP-1 enhances TRIF- and MyD88-dependent transcription of genes encoding IFN-α/β.
Figure 5: SHP-1 inhibits the activation of NF-κB and MAPKs but enhances the TLR-induced activation of STAT1, IRF3 and IRF7.
Figure 6: SHP-1 increases MyD88- and TRIF-dependent IFN-β expression by inhibiting IRAK1 activation.
Figure 7: SHP-1 inhibits IRAK1 activation by directly binding to the IRAK1 kinase domain.
Figure 8: Inactivation of IRAK1 promotes MyD88-, TRIF- and RIG-I-dependent IFN-β expression.
Figure 9: SHP-2 suppresses SHP-1 expression by inhibiting STAT1 activation in MEFs.

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  • 22 December 2010

    In the version of this article initially published, the actin loading control in Figure 6b (left) was incorrect. The correct figure is provided here. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank X. Ma, S. Li and S. Xia for technical assistance; C. Kollewe (Justus-Liebig-University Giessen) for providing IRAK1 expression plasmids; K. Fitzgerald (The University of Massachusetts Medical School) for providing IRF3 and IRF7 reporter plasmids; X. Li (Cleveland Clinic Foundation) for providing IRAK1-deficient and control HEK293 cells; H. Shu (Wuhan University) for providing the RIG-I-N expression plasmid; G.-Sh. Feng (The Burnham Institute) for providing SHP-2–deficient MEFs; and W. Pan (Second Military Medical University) for providing VSV. Supported by the National Natural Science Foundation of China (30490240, 30721091 and 30731160623), the National Key Basic Research Program of China (2007CB512403) and the Shuguang Program of the Shanghai Municipal Education Committee.

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  1. Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, 200433, China

    Huazhang An, Jin Hou, Jun Zhou, Wei Zhao, Hongmei Xu, Yuejuan Zheng, Yizhi Yu, Shuxun Liu & Xuetao Cao

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Contributions

H.A., J.H., J.Z., W.Z., H.X., Y.Z., Y.Y. and S.L. did the experiments; H.A. and X.C. designed the experiments and wrote the paper.

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Correspondence to Xuetao Cao.

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An, H., Hou, J., Zhou, J. et al. Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat Immunol 9, 542–550 (2008). https://doi.org/10.1038/ni.1604

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