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Inhibition of serum‐ and glucocorticoid‐inducible kinase 1 enhances TLR‐mediated inflammation and promotes endotoxin‐driven organ failure
Author(s) -
Zhou Huaxin,
Gao Shegan,
Duan Xiaoxian,
Liang Shuang,
Scott David A.,
Lamont Richard J.,
Wang Huizhi
Publication year - 2015
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/fj.15-270462
Subject(s) - sgk1 , proinflammatory cytokine , inflammation , gene silencing , iκb kinase , kinase , immune system , phosphorylation , cytokine , small interfering rna , nf κb , biology , immunology , microbiology and biotechnology , cancer research , transfection , gene , biochemistry
Serum‐ and glucocorticoid‐regulated kinase (SGK)1 is associated with several important pathologic conditions and plays a modulatory role in adaptive immune responses. However, the involvement and functional role of SGK1 in innate immune responses remain entirely unknown. In this study, we establish that SGK1 is a novel and potent negative regulator of TLR‐induced inflammation. Pharmacologic inhibition of SGK1 or suppression by small interfering RNA enhances proinflammatory cytokine (TNF, IL‐12, and IL‐6) production in TLR‐engaged monocytes, a result confirmed in Cre‐loxP‐mediated SGK1‐deficient cells. SGK1 inhibition or gene deficiency results in increased phosphorylation of IKK, IκBα, and NF‐κB p65 in LPS‐stimulated cells. Enhanced NF‐κB p65 DNA binding also occurs upon SGK1 inhibition. The subsequent enhancement of proinflammatory cytokines is dependent on the phosphorylation of TGF‐β‐activated kinase 1 (TAK1), as confirmed by TAK1 gene silencing. In vivo relevance was established in a murine endotoxin model, in which we found that SGK1 inhibition aggravates the severity of multiple organ damage and enhances the inflammatory response by heightening both proinflammatory cytokine levels and neutrophil infiltration. These findings have identified an anti‐inflammatory function of SGK1, elucidated the underlying intracellular mechanisms, and establish, for the first time, that SGK1 holds potential as a novel target for intervention in the control of inflammatory diseases.—Zhou, H., Gao, S., Duan, X., Liang, S., Scott, D. A., Lamont, R. J., Wang, H. Inhibition of serum‐ and glucocorticoid‐inducible kinase 1 enhances TLR‐mediated inflammation and promotes endotoxin‐driven organ failure. FASEB J. 29, 3737‐3749 (2015). www.fasebj.org