title: Autocrine loop between TGF-beta1 and IL-1beta through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells.
abstract: Pancreatic stellate cells (PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1beta has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1beta secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1beta mRNA and secrete IL-1beta peptide. Inhibition of TGF-beta(1) activity secreted from PSCs by TGF-beta(1)-neutralizing antibody attenuated IL-1beta secretion from PSCs. Exogenous TGF-beta(1) increased IL-1beta expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative (dn)Smad2/3 expression reduced both basal and TGF-beta(1)-stimulated IL-1beta expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1beta expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1beta activity secreted from PSCs by IL-1beta-neutralizing antibody attenuated TGF-beta(1) secretion from PSCs. Exogenous IL-1beta enhanced TGF-beta(1) expression and secretion by PSCs. IL-1beta activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1beta enhancement of TGF-beta(1) expression and secretion by PSCs. We propose that an autocrine loop exists between TGF-beta(1) and IL-1beta in activated PSCs through Smad3- and ERK-dependent pathways.
authors.affiliation: Department of Gastroenterology, Jichi Medical School, 3311-1 Yakushiji, 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: Takako
authors.initials: T
authors.lastname: Ishijima
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Satoh
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Hanatsuka
authors.forename: Akira
authors.initials: A
authors.lastname: Ohashi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Wada
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Miyata
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: Hiroshi
authors.initials: H
authors.lastname: Yasuda
authors.forename: Hirosato
authors.initials: H
authors.lastname: Mashima
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sugano
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D019898:Autocrine Communication; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007375:Interleukin-1; 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