title: Salt-inducible kinase 3 deficiency exacerbates lipopolysaccharide-induced endotoxin shock accompanied by increased levels of pro-inflammatory molecules in mice.
abstract: Macrophages play important roles in the innate immune system during infection and systemic inflammation. When bacterial lipopolysaccharide (LPS) binds to Toll-like receptor 4 on macrophages, several signalling cascades co-operatively up-regulate gene expression of inflammatory molecules. The present study aimed to examine whether salt-inducible kinase [SIK, a member of the AMP-activated protein kinase (AMPK) family] could contribute to the regulation of immune signal not only in cultured macrophages, but also in vivo. LPS up-regulated SIK3 expression in murine RAW264.7 macrophages and exogenously over-expressed SIK3 negatively regulated the expression of inflammatory molecules [interleukin-6 (IL-6), nitric oxide (NO) and IL-12p40] in RAW264.7 macrophages. Conversely, these inflammatory molecule levels were up-regulated in SIK3-deficient thioglycollate-elicited peritoneal macrophages (TEPM), despite no impairment of the classical signalling cascades. Forced expression of SIK3 in SIK3-deficient TEPM suppressed the levels of the above-mentioned inflammatory molecules. LPS injection (10 mg/kg) led to the death of all SIK3-knockout (KO) mice within 48 hr after treatment, whereas only one mouse died in the SIK1-KO (n = 8), SIK2-KO (n = 9) and wild-type (n = 8 or 9) groups. In addition, SIK3-KO bone marrow transplantation increased LPS sensitivity of the recipient wild-type mice, which was accompanied by an increased level of circulating IL-6. These results suggest that SIK3 is a unique negative regulator that suppresses inflammatory molecule gene expression in LPS-stimulated macrophages.
authors.affiliation: Laboratory of Cell Signalling and Metabolic Disease, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Sanosaka
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Ohkawara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagatake
authors.forename: Yumi
authors.initials: Y
authors.lastname: Itoh
authors.forename: Mai
authors.initials: M
authors.lastname: Kagawa
authors.forename: Ayako
authors.initials: A
authors.lastname: Kumagai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fuchino
authors.forename: Jun
authors.initials: J
authors.lastname: Kunisawa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
chemical_list: D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; C571369:SIK3 protein, mouse
keywords: AMP-activated protein kinase; endotoxin shock; inducible nitric oxide synthase; interleukin-12p40; interleukin-1β; interleukin-6; macrophage; salt-inducible kinases; tumour necrosis factor-α