Central Role for Type I Interferons and Tyk2 in Lipopolysaccharide-Induced Endotoxin Shock

Nat Immunol. 2003 May;4(5):471-7. doi: 10.1038/ni910. Epub 2003 Apr 7.

Abstract

Toll-like receptor-4 activation by lipopolysaccharide (LPS) induces the expression of interferon-beta (IFN-beta) in a MyD88-independent manner. Here we report that mice devoid of the JAK protein tyrosine kinase family member, Tyk2, were resistant to shock induced by high doses of LPS. Basal and LPS-induced expression of IFN-beta and IFN-alpha4 mRNA in Tyk2-null macrophages were diminished. However, Tyk2-null mice showed normal systemic production of nitric oxide and proinflammatory cytokines and the in vivo response to tumor necrosis factor (TNF) was unperturbed. IFN-beta-null but not STAT1-null mice were also resistant to high dose LPS treatment. Together, these data suggest that Tyk2 and IFN-beta are essential effectors in LPS induced lethality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / biosynthesis
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factor-7
  • Interferon Type I / genetics*
  • Interferon-alpha / genetics
  • Interferon-beta / genetics
  • Lipopolysaccharides / toxicity
  • Macrophage Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / biosynthesis
  • Phosphoproteins / genetics
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • STAT1 Transcription Factor
  • Shock, Septic / etiology
  • Shock, Septic / genetics
  • Shock, Septic / immunology*
  • TYK2 Kinase
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Cytokines
  • DNA-Binding Proteins
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Interferon-alpha
  • Irf1 protein, mouse
  • Irf7 protein, mouse
  • Lipopolysaccharides
  • Phosphoproteins
  • Proteins
  • RNA, Messenger
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • Nitric Oxide
  • Interferon-beta
  • Protein-Tyrosine Kinases
  • TYK2 Kinase
  • Tyk2 protein, mouse