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Expression of transforming growth factor-ß1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis

Expression of transforming growth factor-ß1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis
Expression of transforming growth factor-ß1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis
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.
0002-9440
1787-1798
Shek, Fanny Wai-Tsing
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Benyon, Robert Christopher
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Walker, Fiona Mairi
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McCrudden, Peter Raymond
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Pender, Sylvia Lin Foon
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Williams, Elizabeth Jean
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Johnson, Penelope Ann
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Johnson, Colin David
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Bateman, Adrian Calvin
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Fine, David Roger
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Iredale, John Peter
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Shek, Fanny Wai-Tsing
ef2490aa-24f1-486a-a424-6d1ec06684f6
Benyon, Robert Christopher
587319e2-6522-4b6e-b4d6-771b080ef919
Walker, Fiona Mairi
58106507-32cb-4bc2-8ebe-1bdd64fcd5bc
McCrudden, Peter Raymond
44ea907f-72fd-4970-bdc7-7556b3a13c61
Pender, Sylvia Lin Foon
62528b03-ec42-41bb-80fe-48454c2c5242
Williams, Elizabeth Jean
e0514824-7dc2-4dd1-87da-3cc010f582f1
Johnson, Penelope Ann
a78f7261-43cd-47a6-9692-7a4a6ff5959a
Johnson, Colin David
e50aa9cd-8c61-4fe3-a0b3-f51cc3a6c74a
Bateman, Adrian Calvin
d97683b1-a5ed-4e85-a985-c0dd71c806f8
Fine, David Roger
ce3d6a77-040e-4aec-a8f5-4c4c22431605
Iredale, John Peter
9d749559-6323-4f25-8f99-617ca840c7c8

Shek, Fanny Wai-Tsing, Benyon, Robert Christopher, Walker, Fiona Mairi, McCrudden, Peter Raymond, Pender, Sylvia Lin Foon, Williams, Elizabeth Jean, Johnson, Penelope Ann, Johnson, Colin David, Bateman, Adrian Calvin, Fine, David Roger and Iredale, John Peter (2002) Expression of transforming growth factor-ß1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. The American Journal of Pathology, 160 (5), 1787-1798. (doi:10.1016/S0002-9440(10)61125-X). (PMID:12000730)

Record type: Article

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-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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Published date: May 2002
Organisations: Medical Education

Identifiers

Local EPrints ID: 353737
URI: http://eprints.soton.ac.uk/id/eprint/353737
ISSN: 0002-9440
PURE UUID: 8d59447c-cb7b-40eb-823a-2a3561b18e7b
ORCID for Sylvia Lin Foon Pender: ORCID iD orcid.org/0000-0001-6332-0333

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Date deposited: 14 Jun 2013 14:30
Last modified: 15 Mar 2024 03:08

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Contributors

Author: Fanny Wai-Tsing Shek
Author: Robert Christopher Benyon
Author: Fiona Mairi Walker
Author: Peter Raymond McCrudden
Author: Elizabeth Jean Williams
Author: Penelope Ann Johnson
Author: Adrian Calvin Bateman
Author: David Roger Fine
Author: John Peter Iredale

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