Inhibition of serum- and glucocorticoid-inducible kinase 1 enhances TLR-mediated inflammation and promotes endotoxin-driven organ failure

摘要: Serum- and glucocorticoid-regulated kinase (SGK)1 is associated with several important pathologic conditions plays a modulatory role in adaptive immune responses. However, the involvement functional of SGK1 innate responses remain entirely unknown. In this study, we establish that novel potent negative regulator TLR-induced inflammation. Pharmacologic inhibition or suppression by small interfering RNA enhances proinflammatory cytokine (TNF, IL-12, IL-6) production TLR-engaged monocytes, result confirmed Cre-loxP-mediated SGK1-deficient cells. gene deficiency results increased phosphorylation IKK, IκBα, NF-κB p65 LPS-stimulated Enhanced DNA binding also occurs upon inhibition. The subsequent enhancement cytokines dependent on TGF-β-activated 1 (TAK1), as TAK1 silencing. vivo relevance was established murine endotoxin model, which found aggravates severity multiple organ damage inflammatory response heightening both levels neutrophil infiltration. These findings have identified an anti-inflammatory function SGK1, elucidated underlying intracellular mechanisms, establish, for first time, holds potential target intervention control diseases.