Abstract
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.
MeSH terms
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Animals
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Chemokine CXCL1
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Chemokine CXCL10
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Chemokines
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Chemokines, CXC / biosynthesis
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Chemokines, CXC / genetics
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Cytokines / biosynthesis
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Cytokines / genetics
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DNA / metabolism
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Enzyme Induction / drug effects
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Gene Expression Regulation / drug effects*
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Interferon Regulatory Factor-1
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Lipopolysaccharides / pharmacology*
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Macrophages, Peritoneal / drug effects*
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / metabolism
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type II
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Phosphoproteins / biosynthesis
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Phosphoproteins / genetics
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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STAT1 Transcription Factor
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Specific Pathogen-Free Organisms
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription, Genetic / drug effects*
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
Substances
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Chemokine CXCL1
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Chemokine CXCL10
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Chemokines
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Chemokines, CXC
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Cxcl1 protein, mouse
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Cytokines
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DNA-Binding Proteins
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Interferon Regulatory Factor-1
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Irf1 protein, mouse
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Lipopolysaccharides
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NF-kappa B
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Phosphoproteins
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RNA, Messenger
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STAT1 Transcription Factor
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Stat1 protein, mouse
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Trans-Activators
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Tumor Necrosis Factor-alpha
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keratinocyte-derived chemokines
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DNA
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse