Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines

被引：36

作者：

Aoki, Hiroyoshi ^{[1
]}

Ohnishi, Hirohide ^{[1
]}

Hama, Kouji ^{[1
]}

Shinozaki, Satoshi ^{[1
]}

Kita, Hiroto ^{[1
]}

Osawa, Hiroyuki ^{[1
]}

Yamamoto, Hironori ^{[1
]}

Sato, Kiichi ^{[1
]}

Tamada, Kiichi ^{[1
]}

Sugano, Kentaro ^{[1
]}

机构：

[1] Jichi Med Sch, Dept Gastroenterol, Kawachi, Tochigi 3290498, Japan

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2007年 / 292卷 / 01期

关键词：

transforming growth factor-beta; interleukin; Smad; autocrine; pancreatic fibrosis;

D O I：

10.1152/ajpcell.00030.2006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines. Am J Physiol Cell Physiol 292: C259-C268, 2007. First published July 12, 2006; doi:10.1152/ajpcell.00030.2006.-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-beta 1, IL-beta, 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-beta 1, IL-1 beta, 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-beta 1 in activated PSCs. Moreover, dominant negative Smad2/3 expression attenuated the expression of COX-2 and alpha-SMA enhanced by IL-1 beta and IL-6. Anti-TGF-beta neutralizing antibody also attenuated the increase in COX- 2 and alpha-SMA expression caused by IL-1 beta and IL-6. IL-6 as well as IL-1 beta enhanced TGF-beta 1 secretion from PSCs. These data indicate that Smad2/3-dependent pathway plays a central role in COX-2 induction by TGF-beta 1, IL-1 beta , and IL-6. Furthermore, IL-1 beta and IL- 6 promote PSC activation by enhancing COX- 2 expression indirectly through Smad2/3-dependent pathway by increasing TGF-beta 1 secretion from PSCs.

引用

页码：C259 / C268

页数：10

共 28 条

[1] Autocrine loop between TGF-β1 and IL-1β through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells [J].

Aoki, H ;

Ohnishi, H ;

Hama, K ;

Ishijima, T ;

Satoh, Y ;

Hanatsuka, K ;

Ohashi, A ;

Wada, S ;

Miyata, T ;

Kita, H ;

Yamamoto, H ;

Osawa, H ;

Sato, K ;

Tamada, K ;

Yasuda, H ;

Mashima, H ;

Sugano, K .

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2006, 290 (04) :C1100-C1108

[2] Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis [J].

Apte, MV ;

Haber, PS ;

Darby, SJ ;

Rodgers, SC ;

McCaughan, GW ;

Korsten, MA ;

Pirola, RC ;

Wilson, JS .

GUT, 1999, 44 (04) :534-541

[3] Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture [J].

Apte, MV ;

Haber, PS ;

Applegate, TL ;

Norton, ID ;

McCaughan, GW ;

Korsten, MA ;

Pirola, RC ;

Wilson, JS .

GUT, 1998, 43 (01) :128-133

[4] Signal transduction by the TGF-β superfamily [J].

Attisano, L ;

Wrana, JL .

SCIENCE, 2002, 296 (5573) :1646-1647

[5] Identification, culture, and characterization of pancreatic stellate cells in rats and humans [J].

Bachem, MG ;

Schneider, E ;

Gross, H ;

Weidenbach, H ;

Schmid, RM ;

Menke, A ;

Siech, M ;

Beger, H ;

Grünert, A ;

Adler, G .

GASTROENTEROLOGY, 1998, 115 (02) :421-432

[6] Pancreas: Healing response in critical illness [J].

Bentrem, DJ ;

Joehl, RJ .

CRITICAL CARE MEDICINE, 2003, 31 (08) :S582-S589

[7] Role of p38 MAP kinases and ERK in mediating ultraviolet-B induced cyclooxygenase-2 gene expression in human keratinocytes [J].

Chen, WX ;

Tang, QB ;

Gonzales, MS ;

Bowden, GT .

ONCOGENE, 2001, 20 (29) :3921-3926

[8] Inhibition of the expression of α-smooth muscle actin in human hepatic stellate cell line, L190, by a selective cyclooxygenase 2 inhibitor, NS-398 [J].

Cheng, JD ;

Imanishi, H ;

Liu, WD ;

Iwasaki, A ;

Ueki, N ;

Nakamura, H ;

Hada, T .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2002, 297 (05) :1128-1134

[9] Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention [J].

Chun, KS ;

Surh, YJ .

BIOCHEMICAL PHARMACOLOGY, 2004, 68 (06) :1089-1100

[10] Involvement of NF-kappa B in the regulation of cyclooxygenase-2 protein expression in LPS-stimulated J774 macrophages [J].

DAcquisto, F ;

Iuvone, T ;

Rombola, L ;

Sautebin, L ;

DiRosa, M ;

Carnuccio, R .

FEBS LETTERS, 1997, 418 (1-2) :175-178

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