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MKP‐1 inhibits iNOS expression during the innate immune response to LPS
Author(s) -
Liu Yusen,
Zhao Qun,
Wang Xianxi,
Nelin Leif D.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.675.2
Subject(s) - nitric oxide synthase , biology , innate immune system , septic shock , immunology , immune system , knockout mouse , stat1 , nitric oxide , inflammation , sepsis , signal transduction , microbiology and biotechnology , endocrinology , gene , biochemistry
Nitric oxide (NO) is a potent antimicrobial substance and a powerful vasodilator. Inducible NO synthase (iNOS) is responsible for the substantial NO production that occurs with microbial infection. Induction of iNOS in macrophages plays a critical role for the eradication of intracellular pathogens. Moreover, the excessive production of NO by iNOS has also been implicated in the pathogenesis of septic shock syndrome. Previously, we have demonstrated that mice deficient in mitogen‐activated protein kinase phosphatase ( Mkp )‐ 1 exhibit exaggerated inflammatory responses and rapidly succumb to lipopolysaccharides (LPS). In response to LPS, Mkp‐1 −/− mice produce greater amounts of inflammatory cytokines and NO than wild type mice, and exhibit severe hypotension. To understand the molecular basis for the increases in NO production, we studied the role of Mkp‐1 in the regulation of iNOS expression. We found that LPS challenge elicited a stronger iNOS induction in Mkp‐1 knockout mice than in wild type mice. Likewise, LPS treatment also resulted in greater iNOS expression in Mkp‐1 −/− macrophages than in wild type cells. Both accelerated gene transcription and enhanced mRNA stability contribute to the increases in iNOS expression in LPS‐stimulated Mkp‐1 −/− macrophages. We found that two transcription factors known to mediate iNOS induction, Stat1 and IRF1, were more potently activated by LPS in Mkp‐1 −/− macrophages than in wild type cells, explaining the accelerated iNOS gene transcription in the Mkp‐1 −/− cells. Our results suggest that augmentation of MKP‐1 expression may be a novel treatment for patients suffering from sepsis and septic shock.