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

Abstract

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-loxPmediated SGK1-deficient cells. SGK1 inhibition or gene deficiency results in increased phosphorylation of IKK, IkBa, and NF-kB p65 in LPS-stimulated cells. Enhanced NF-kB p65 DNA binding also occurs upon SGK1 inhibition. The subsequent enhancement of proinflammatory cytokines is dependent on the phosphorylation of TGF-b-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.-

Resolvin D1, resolvin D2 and maresin 1 activate the GSK3β anti-inflammatory axis in TLR4-engaged human monocytes

“…Interestingly, the activation state of SGK1, which we have recently established to be a potent anti-inflammatory mediator in the context of TLR-engagement, 3 was also enhanced by MaR1, RVD1 and RVD2. However, the phosphorylation state of SYK, a TLR ligand and inflammatory enhancer, 43 and several MAPK-related molecules was not influenced by resolvins.…”

“…The activation status of SGK1, an anti-inflammatory kinase, 3 was similarly enhanced. Phosphorylation of SYK, a TLR ligand and inflammatory enhancer, 43 pERK1/2, pSAPK/JNK and/or p38 MAPK were unaffected (data not shown).…”

Serum- and glucocorticoid-inducible kinases in microglia

“…Since SGKs are implicated in inflammatory responses in some immune cells [13,14], we tested whether they play a role in microglial activation and inflammatory responses. In BV-2 cells stimulated with LPS, we found that the levels of gene expression of inflammatory mediators, iNOS and TNFα, were upregulated (Fig.…”

“…Given the fact that inflammatory factors are facilitated by SGK inhibition and that NF-κB signaling is regulated by SGK1 in other immune cells [13,14], we inspected the effect of SGK inhibition on NF-κB signaling. First, we probed nuclear translocation of NF-κB by LPS application and found that fluorescent signals of NF-κB seemed to be more intensive in nuclei in the presence of gsk650394 (Fig.…”

“…Also, inhibition of SGK1 affects neutrophil chemotaxis [12]. In addition, recent studies have found SGK1 to be implicated in NF-κB activity, and that the regulated NF-κB signaling is associated with immunological significances such as inflammatory responses in monocytes and differentiation of dendritic cells [13,14]. …”