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(American Journal of Pathology. 2002;160:1787-1798.)
© 2002 American Society for Investigative Pathology

Regular Articles

Expression of Transforming Growth Factor-ß1 by Pancreatic Stellate Cells and Its Implications for Matrix Secretion and Turnover in Chronic Pancreatitis

Fanny Wai-Tsing Shek^*, Robert Christopher Benyon^*, Fiona Mairi Walker^*, Peter Raymond McCrudden^*, Sylvia Lin Foon Pender^*, Elizabeth Jean Williams^*, Penelope Ann Johnson^*, Colin David Johnson, Adrian Calvin Bateman, David Roger Fine^* and John Peter Iredale^*

From the Divisions of Infection, Inflammation, and Repair,^*Cellular Pathology,and Cancer Sciences,University of Southampton, Southampton General Hospital, Southampton, United Kingdom

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-ß (TGF-ß) 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-ß1. 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-ß1 constitutes 2 to 5% of total TGF-ß1 secreted by pancreatic stellate cells; they express TGF-ß receptors I and II. Exogenous TGF-ß1 (10 ng/ml) significantly increased procollagen-1 mRNA by 69% and collagen protein synthesis by 34%. Similarly TGF-ß1 at 0.1, 1, and 10 ng/ml significantly reduced cellular proliferation rate by 37%, 44%, and 44%, respectively, whereas pan-TGF-ß-neutralizing antibody increased proliferation by 40%. TGF-ß1 (10 ng/ml) down-regulated MMP-9 by 54% and MMP-3 by 34% whereas TGF-ß1-neutralizing antibody increased MMP-9 expression by 39%. Pancreatic stellate cells express both mediators of matrix remodeling and the regulatory cytokine TGF-ß1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation.

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