title: Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis.
abstract: Pancreatic stellate cells mediate fibrosis in chronic pancreatitis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs)-1 and -2 are crucial modulators of fibrosis. Transforming growth factor-beta (TGF-beta) is a key regulator of extracellular matrix production and myofibroblast proliferation. We have examined MMP and TIMP synthesis by transformed cultured pancreatic stellate cells and their regulation by TGF-beta 1. By Northern analysis they expressed mRNAs for procollagen 1, TIMP-1, TIMP-2, and MMP-2. Expression of membrane type-1 MMP was confirmed by Western blotting. By immunohistochemistry these enzymes localized to fibrotic areas in human chronic pancreatitis. Active TGF-beta 1 constitutes 2 to 5% of total TGF-beta 1 secreted by pancreatic stellate cells; they express TGF-beta receptors I and II. Exogenous TGF-beta 1 (10 ng/ml) significantly increased procollagen-1 mRNA by 69% and collagen protein synthesis by 34%. Similarly TGF-beta 1 at 0.1, 1, and 10 ng/ml significantly reduced cellular proliferation rate by 37%, 44%, and 44%, respectively, whereas pan-TGF-beta-neutralizing antibody increased proliferation by 40%. TGF-beta1 (10 ng/ml) down-regulated MMP-9 by 54% and MMP-3 by 34% whereas TGF-beta 1-neutralizing antibody increased MMP-9 expression by 39%. Pancreatic stellate cells express both mediators of matrix remodeling and the regulatory cytokine TGF-beta 1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation.
authors: Divisions of Infection, Inflammation, and Repair, Cellular Pathology, and Cancer Sciences, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
authors: Fanny Wai-Tsing
authors: FW
authors: Shek
authors: Robert Christopher
authors: RC
authors: Benyon
authors: Fiona Mairi
authors: FM
authors: Walker
authors: Peter Raymond
authors: PR
authors: McCrudden
authors: Sylvia Lin Foon
authors: SL
authors: Pender
authors: Elizabeth Jean
authors: EJ
authors: Williams
authors: Penelope Ann
authors: PA
authors: Johnson
authors: Colin David
authors: CD
authors: Johnson
authors: Adrian Calvin
authors: AC
authors: Bateman
authors: David Roger
authors: DR
authors: Fine
authors: John Peter
authors: JP
authors: Iredale
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009130:Muscle, Smooth / Q000737:chemistry; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D010195:Pancreatitis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D000199:Actins; D024042:Collagen Type I; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019716:Tissue Inhibitor of Metalloproteinase-2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9