Requirement for STAT1 in LPS-induced gene expression in macrophages.
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.
Ohmori
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Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Ohio 44195, USA. ohmorih@ccf.org
Hamilton
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D000818:Animals; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050794:STAT1 Transcription Factor; D013047:Specific Pathogen-Free Organisms; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010750:Phosphoproteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; C074302:keratinocyte-derived chemokines; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse