title: Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines.
abstract: Cyclooxygenase-2 (COX-2) mediates various inflammatory responses and is expressed in pancreatic tissue from patients with chronic pancreatitis. To examine the role of COX-2 in chronic pancreatitis, we investigated its participation in regulating functions of pancreatic stellate cells (PSCs), using isolated rat PSCs. COX-2 was expressed in culture-activated PSCs but not in freshly isolated quiescent PSCs. TGF-beta1, IL-1beta, and IL-6 enhanced COX-2 expression in activated PSCs, concomitantly increasing the expression of alpha-smooth muscle actin (alpha-SMA), a parameter of PSC activation. The COX-2 inhibitor NS-398 blocked culture activation of freshly isolated quiescent PSCs. NS-398 also inhibited the enhancement of alpha-SMA expression by TGF-beta1, IL-1beta, and IL-6 in activated PSCs. These data indicate that COX-2 is required for the initiation and promotion of PSC activation. We further investigated the mechanism by which cytokines enhance COX-2 expression in PSCs. Adenovirus-mediated expression of dominant negative Smad2/3 inhibited the increase in expression of COX-2, alpha-SMA, and collagen-1 mediated by TGF-beta1 in activated PSCs. Moreover, dominant negative Smad2/3 expression attenuated the expression of COX-2 and alpha-SMA enhanced by IL-1beta and IL-6. Anti-TGF-beta neutralizing antibody also attenuated the increase in COX-2 and alpha-SMA expression caused by IL-1beta and IL-6. IL-6 as well as IL-1beta enhanced TGF-beta1 secretion from PSCs. These data indicate that Smad2/3-dependent pathway plays a central role in COX-2 induction by TGF-beta1, IL-1beta, and IL-6. Furthermore, IL-1beta and IL-6 promote PSC activation by enhancing COX-2 expression indirectly through Smad2/3-dependent pathway by increasing TGF-beta1 secretion from PSCs.
authors.affiliation: Department of Gastroenterology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-cho, Kawachi-gun, Tochigi 329-0498, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Aoki
authors.forename: Hirohide
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Kouji
authors.initials: K
authors.lastname: Hama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shinozaki
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osawa
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kiichi
authors.initials: K
authors.lastname: Sato
authors.forename: Kiichi
authors.initials: K
authors.lastname: Tamada
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sugano
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology*; D005799:Genes, Dominant; D018836:Inflammation Mediators / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009130:Muscle, Smooth / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D051899:Smad2 Protein / Q000235:genetics / Q000494:pharmacology; D051900:Smad3 Protein / Q000235:genetics / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism / Q000502:physiology
chemical_list: D000199:Actins; D000906:Antibodies; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D009578:Nitrobenzenes; D047428:Protein Kinase Inhibitors; D051899:Smad2 Protein; D051900:Smad3 Protein; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases