title: Existence of autocrine loop between interleukin-6 and transforming growth factor-beta1 in activated rat pancreatic stellate cells.
abstract: Interleukin (IL)-6 is a proinflammatory cytokine assumed to participate in pancreatic fibrosis by activating pancreatic stellate cells (PSCs). Autocrine TGF-beta1 is to central in PSC functional regulation. In this study, we examined IL-6 secretion from culture-activated rat PSCs and its regulatory mechanism. Activated PSCs express and secrete IL-6. When anti-TGF-beta1 neutralizing antibody was added in the culture medium, IL-6 secretion from activated PSCs was inhibited, whereas exogenous TGF-beta1 added in the culture medium enhanced IL-6 expression and secretion by PSCs in a dose dependent manner. Infection of PSCs with an adenovirus expressing dominant-negative Smad2/3 attenuated basal and TGF-beta1-stimulated IL-6 expression and secretion of PSCs. We also demonstrated the reciprocal effect of PSCs-secreted IL-6 on autocrine TGF-beta1. Anti-IL-6 neutralizing antibody inhibited TGF-beta1 secretion from PSCs. Preincubation of cells with 10 nM PD98059, an extracellular signal-regulated kinase (ERK)-dependent pathway inhibitor, attenuated IL-6-enhanced TGF-beta1 expression and secretion of PSCs. In addition, IL-6 activated ERK in PSCs. These data indicate the existence of autocrine loop between IL-6 and TGF-beta1 through ERK- and Smad2/3-dependent pathways in activated PSCs.
authors.affiliation: Department of Gastroenterology, Jichi Medical School, Tochigi, 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: Hironori
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osawa
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: D000818:Animals; D019898:Autocrine Communication; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D051899:Smad2 Protein / Q000187:drug effects / Q000378:metabolism; D051900:Smad3 Protein / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D015850:Interleukin-6; D012333:RNA, Messenger; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one