title: Activation of phosphoinositide 3-kinase in response to inflammation and nitric oxide leads to the up-regulation of cyclooxygenase-2 expression and subsequent cell proliferation in mesangial cells.
abstract: In this study, we showed that nitric oxide (NO) donors induced the mesangial cell proliferation and cyclooxygenase-2 (COX-2) protein expression in murine mesangial cells. An inflammatory condition [lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma)] could also induce cell proliferation and significantly enhance inducible nitric oxide synthase (iNOS) and COX-2 expression. Phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, inhibited these responses. LPS/IFN-gamma-induced COX-2 expression in mesangial cells could be inhibited by iNOS inhibitor, aminoguanidine. Selective COX-2 inhibitor, NS398, was capable of inhibiting NO donor- or LPS/IFN-gamma-induced mesangial cell proliferation. Both NO donor and LPS/IFN-gamma markedly activated the PI3K activity and the phosphorylation of Akt and nuclear factor (NF)-kappaB DNA binding activity in mesangial cells, which could be inhibited by LY294002 and transfection of dominant-negative vectors of PI3K/p85 and Akt. These results indicate that a PI3K/Akt-dependent pathway involved in the NO-regulated COX-2 expression and cell proliferation in mesangial cells under inflammatory condition.
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei.
authors.forename: Meei Ling
authors.initials: ML
authors.lastname: Sheu
authors.forename: Kuo Fang
authors.initials: KF
authors.lastname: Chao
authors.forename: Yen Jen
authors.initials: YJ
authors.lastname: Sung
authors.forename: Wan Wan
authors.initials: WW
authors.lastname: Lin
authors.forename: Shoei Yn
authors.initials: SY
authors.lastname: Lin-Shiau
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D005799:Genes, Dominant; D005822:Genetic Vectors; D005920:Glomerular Mesangium / Q000166:cytology* / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology; D051550:I-kappa B Kinase; D015151:Immunoblotting; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D002867:Chromones; D051546:Cyclooxygenase 2; D006146:Guanidines; D051550:I-kappa B Kinase; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D009025:Morpholines; D016328:NF-kappa B; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites; D009578:Nitrobenzenes; D019869:Phosphatidylinositol 3-Kinases; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496317:Nos2 protein, mouse; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C004479:pimagedine