Inhibition of serum- and glucocorticoid-inducible kinase 1 enhances TLR-mediated inflammation and promotes endotoxin-driven organ failure
| Autor: | Shegan Gao, Xiaoxian Duan, Huizhi Wang, Richard J. Lamont, Shuang Liang, Huaxin Zhou, David A. Scott |
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| Rok vydání: | 2015 |
| Předmět: |
Lipopolysaccharides
Male Multiple Organ Failure Mice Transgenic Inflammation IκB kinase Protein Serine-Threonine Kinases Biology Biochemistry Immediate-Early Proteins Proinflammatory cytokine Research Communication Mice Immune system Genetics medicine Animals Humans RNA Small Interfering Molecular Biology Innate immune system urogenital system Toll-Like Receptors Transcription Factor RelA MAP Kinase Kinase Kinases I-kappa B Kinase IκBα Immunology SGK1 Cancer research Cytokines Female Tumor necrosis factor alpha medicine.symptom Biotechnology |
| Zdroj: | The FASEB Journal. 29:3737-3749 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.15-270462 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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