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Requirement for STAT1 in LPS‐induced gene expression in macrophages
Author(s) -
Ohmori Yoshihiro,
Hamilton Thomas A.
Publication year - 2001
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.69.4.598
Subject(s) - stat1 , biology , stat protein , lipopolysaccharide , microbiology and biotechnology , tumor necrosis factor alpha , gene expression , chemokine , transcription factor , interferon , nitric oxide synthase , regulation of gene expression , interferon gamma , signal transduction , innate immune system , cytokine , stat3 , immunology , nitric oxide , gene , immune system , endocrinology , biochemistry
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 α 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 κB. LPS stimulated the delayed activation of both IFN‐stimulated response element and IFN‐γ‐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‐α/βR−/− 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.