title: 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-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.
authors.affiliation: *Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA; Department of Oncology, Cancer Institute, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: *Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA; Department of Oncology, Cancer Institute, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Shegan
authors.initials: S
authors.lastname: Gao
authors.affiliation: *Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA; Department of Oncology, Cancer Institute, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Duan
authors.affiliation: *Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA; Department of Oncology, Cancer Institute, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.affiliation: *Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA; Department of Oncology, Cancer Institute, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: *Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA; Department of Oncology, Cancer Institute, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA rich.lamont@louisville.edu hhwang01@louisville.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lamont
authors.affiliation: *Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA; Department of Oncology, Cancer Institute, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA rich.lamont@louisville.edu hhwang01@louisville.edu.
authors.forename: Huizhi
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D051550:I-kappa B Kinase; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099151:MAP Kinase Kinase Kinase 7; C498143:RELA protein, human; C498144:Rela protein, mouse; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496562:Ikbkb protein, mouse
keywords: LPS; SGK1; TAK1; inflammatory cytokines