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

Nat Immunol. 2008 May;9(5):542-50. doi: 10.1038/ni.1604. Epub 2008 Apr 6.

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-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain / physiology
  • Cytokines / biosynthesis
  • Homeostasis / immunology
  • Immunity, Innate
  • Interferon Regulatory Factor-1 / metabolism
  • Interferon Type I / biosynthesis*
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors
  • Interleukin-1 Receptor-Associated Kinases / chemistry
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Macrophages, Peritoneal
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / immunology
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Signal Transduction
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism*

Substances

  • Cytokines
  • Interferon Regulatory Factor-1
  • Interferon Type I
  • Membrane Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Robo3 protein, mouse
  • Toll-Like Receptors
  • Interleukin-1 Receptor-Associated Kinases
  • Irak1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6