title: Critical roles of the p110 beta subtype of phosphoinositide 3-kinase in lipopolysaccharide-induced Akt activation and negative regulation of nitrite production in RAW 264.7 cells.
abstract: It has been suggested that PI3K participates in TLR signaling. However, identifying specific roles for individual PI3K subtypes in signaling has remained elusive. In macrophages from the p110gamma(-/-) mouse, LPS-induced phosphorylation of Akt occurred normally despite the fact that the action of anaphylatoxin C5a was impaired markedly. In RAW 264.7 cells expressing short hairpin RNA that targets p110beta, LPS-induced phosphorylation of Akt was significantly attenuated. In contrast, the LPS action was not impaired, but was rather augmented in the p110alpha-deficient cells. Previous pharmacologic studies have suggested that a PI3K-Akt pathway negatively regulates TLR-induced inducible NO synthase expression and cytokine production. In the p110beta-deficient cells, inducible NO synthase expression and IL-12 production upon stimulation by LPS were increased, whereas LPS-induced expression of COX-2 and activation of MAPKs were unaffected. Together, the results suggest a specific function of p110beta in the negative feedback regulation of TLR signaling.
authors.affiliation: Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hazeki
authors.forename: Megumi
authors.initials: M
authors.lastname: Hoshi
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nigorikawa
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Inoue
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Hazeki
mesh_terms: D000818:Animals; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D009573:Nitrites / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D007527:Isoenzymes; D008070:Lipopolysaccharides; D009573:Nitrites; D051193:Toll-Like Receptors; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt