Requirement for STAT1 in LPS-induced gene expression in macrophages

J Leukoc Biol. 2001 Apr;69(4):598-604.


This study examines the role of the signal transducer and activator of transcription 1 (STAT1) in induction of lipopolysaccharide (LPS)-stimulated gene expression both in vitro and in vivo. LPS-induced expression of an interferon (IFN)-inducible 10-kDa protein (IP-10), IFN regulatory factor-1 (IRF-1), and inducible nitric oxide synthase (iNOS) mRNAs was severely impaired in macrophages prepared from Stat1-/- mice, whereas levels of tumor necrosis factor alpha and KC (a C-X-C chemokine) mRNA in LPS-treated cell cultures were unaffected. A similar deficiency in LPS-induced gene expression was observed in livers and spleens from Stat1-/- mice. The reduced LPS-stimulated gene expression seen in Stat1-/- macrophages was not the result of reduced activation of nuclear factor kappaB. LPS stimulated the delayed activation of both IFN-stimulated response element and IFN-gamma-activated sequence binding activity in macrophages from wild-type mice. Activation of these STAT1-containing transcription factors was mediated by the intermediate induction of type I IFNs, since the LPS-induced IP-10, IRF-1, and iNOS mRNA expression was markedly reduced in macrophages from IFN-alpha/betaR-/- mice and blocked by cotreatment with antibodies against type I IFN. These results indicate that indirect activation of STAT1 by LPS-induced type I IFN participates in promoting optimal expression of LPS-inducible genes, and they suggest that STAT1 may play a critical role in innate immunity against gram-negative bacterial infection.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Chemokine CXCL1
  • Chemokine CXCL10
  • Chemokines
  • Chemokines, CXC / biosynthesis
  • Chemokines, CXC / genetics
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • DNA / metabolism
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Enzyme Induction / drug effects
  • Gene Expression Regulation / drug effects*
  • Interferon Regulatory Factor-1
  • Lipopolysaccharides / pharmacology*
  • Macrophages, Peritoneal / drug effects*
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • STAT1 Transcription Factor
  • Specific Pathogen-Free Organisms
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transcription, Genetic / drug effects*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics


  • Chemokine CXCL1
  • Chemokine CXCL10
  • Chemokines
  • Chemokines, CXC
  • Cxcl1 protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Interferon Regulatory Factor-1
  • Irf1 protein, mouse
  • Lipopolysaccharides
  • NF-kappa B
  • Phosphoproteins
  • RNA, Messenger
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • keratinocyte-derived chemokines
  • DNA
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse