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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Actins / metabolism
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Animals
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Blotting, Northern
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Blotting, Western
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Cell Division / genetics
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Cell Division / physiology
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Cells, Cultured
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Chronic Disease
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Collagen Type I / genetics
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Collagen Type I / metabolism
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Down-Regulation
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Extracellular Matrix / metabolism*
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Gene Expression
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Humans
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 3 / genetics
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Matrix Metalloproteinase 3 / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases / genetics
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Metalloendopeptidases / metabolism
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Muscle, Smooth / chemistry
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Pancreas / cytology
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Pancreas / metabolism*
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Pancreatitis / genetics
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Pancreatitis / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Tissue Inhibitor of Metalloproteinase-2 / genetics
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta1
Substances
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Actins
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Collagen Type I
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RNA, Messenger
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Receptors, Transforming Growth Factor beta
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TGFB1 protein, human
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Tgfb1 protein, rat
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Tissue Inhibitor of Metalloproteinase-1
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tissue Inhibitor of Metalloproteinase-2
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9