title: Interleukin-1beta-induced cyclooxygenase-2 expression is mediated through activation of p42/44 and p38 MAPKS, and NF-kappaB pathways in canine tracheal smooth muscle cells.
abstract: Interleukin-beta (IL-1beta) was found to induce inflammatory responses in the airways, which exerted a potent stimulus for PG synthesis. This study was to determine the mechanisms of IL-1beta-enhanced cyclooxygenase (COX)-2 expression associated with PGE(2) synthesis in tracheal smooth muscle cells (TSMCs). IL-1beta markedly increased COX-2 expression and PGE(2) formation in a time- and concentration-dependent manner in TSMCs. Both COX-2 expression and PGE(2) formation in response to IL-1beta were attenuated by a tyrosine kinase inhibitor, genistein, a phosphatidylcholine-phospholipase C inhibitor, D609, a phosphatidylinositol-phospholipase C inhibitor, U73122, protein kinase C inhibitors, GF109203X and staurosporine, removal of Ca(2+) by addition of BAPTA/AM plus EGTA, and phosphatidylinositol 3-kinase (PI3-K) inhibitors, LY294002 and wortmannin. IL-1beta-induced activation of NF-kappaB correlated with the degradation of IkappaB-alpha in TSMCs. IL-1beta-induced NF-kappaB activation, COX-2 expression, and PGE(2) synthesis were inhibited by the dominant negative mutants of NIK and IKK-alpha, but not by IKK-beta. IL-1beta-induced COX-2 expression and PGE(2) synthesis were completely inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 inhibitor), but these two inhibitors had no effect on IL-1beta-induced NF-kappaB activation, indicating that activation of p42/44 and p38 MAPK and NF-kappaB signalling pathways were independently required for these responses. These findings suggest that the increased expression of COX-2 correlates with the release of PGE(2) from IL-1beta-challenged TSMCs, at least in part, independently mediated through MAPKs and NF-kappaB signalling pathways in canine TSMCs. IL-1beta-mediated responses were modulated by PLC, Ca(2+), PKC, tyrosine kinase, and PI3-K in these cells.
authors.affiliation: Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan. chuenmao@mail.cgu.edu.tw
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
authors.forename: Chin-Sung
authors.initials: CS
authors.lastname: Chien
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Luo
authors.forename: Chuan-Chwan
authors.initials: CC
authors.lastname: Wang
mesh_terms: D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D004285:Dogs; D005260:Female; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011014:Pneumonia / Q000201:enzymology / Q000503:physiopathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000201:enzymology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D051546:Cyclooxygenase 2; D015232:Dinoprostone; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D010738:Type C Phospholipases