TGF-β signaling preserves RECK expression in activated pancreatic stellate cells
Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis, but the detailed mechanism for dysregulated accumulation of extracellular matrix (ECM) remains unclear. Cultured rat PSCs become activated by profibrogenic mediators, but these mediators failed...
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Veröffentlicht in: | Journal of cellular biochemistry 2008-06, Vol.104 (3), p.1065-1074 |
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creator | Lee, Hongsik Lim, Chaeseung Lee, Jungeun Kim, Nayoung Bang, Sangsu Lee, Hojae Min, Bonhong Park, Gilhong Noda, Makoto Stetler-Stevenson, William G. Oh, Junseo |
description | Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis, but the detailed mechanism for dysregulated accumulation of extracellular matrix (ECM) remains unclear. Cultured rat PSCs become activated by profibrogenic mediators, but these mediators failed to alter the expression levels of matrix metalloproteinases (MMPs) to the endogenous tissue inhibitors of metalloproteinases (TIMPs). Here, we examined the expression of RECK, a novel membrane‐anchored MMP inhibitor, in PSCs. Although RECK mRNA levels were largely unchanged, RECK protein expression was barely detected at 2, 5 days after plating PSCs, but appeared following continued in vitro culture and cell passage which result in PSC activation. When PSCs at 5 days after plating (PSCs‐5d) were treated with pepstatin A, an aspartic protease inhibitor, or TGF‐β1, a profibrogenic mediator, RECK protein was detected in whole cell lysates. Conversely, Smad7 overexpression or suppression of Smad3 expression in PSCs after passage 2 (PSCs‐P2) led to the loss of RECK protein expression. These findings suggest that RECK is post‐translationally processed in pre‐activated PSCs but protected from proteolytic degradation by TGF‐β signaling. Furthermore, collagenolytic activity of PSCs‐5d was greatly reduced by TGF‐β1, whereas that of PSCs‐P2 was increased by anti‐RECK antibody. Increased RECK levels were also observed in cerulein‐induced acute pancreatitis. Therefore, our results suggest for the first time proteolytic processing of RECK as a mechanism regulating RECK activity, and demonstrate that TGF‐β signaling in activated PSCs may promote ECM accumulation via a mechanism that preserves the protease inhibitory activity of RECK. J. Cell. Biochem. 104: 1065–1074, 2008. © 2008 Wiley‐Liss, Inc. |
doi_str_mv | 10.1002/jcb.21692 |
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Cultured rat PSCs become activated by profibrogenic mediators, but these mediators failed to alter the expression levels of matrix metalloproteinases (MMPs) to the endogenous tissue inhibitors of metalloproteinases (TIMPs). Here, we examined the expression of RECK, a novel membrane‐anchored MMP inhibitor, in PSCs. Although RECK mRNA levels were largely unchanged, RECK protein expression was barely detected at 2, 5 days after plating PSCs, but appeared following continued in vitro culture and cell passage which result in PSC activation. When PSCs at 5 days after plating (PSCs‐5d) were treated with pepstatin A, an aspartic protease inhibitor, or TGF‐β1, a profibrogenic mediator, RECK protein was detected in whole cell lysates. Conversely, Smad7 overexpression or suppression of Smad3 expression in PSCs after passage 2 (PSCs‐P2) led to the loss of RECK protein expression. These findings suggest that RECK is post‐translationally processed in pre‐activated PSCs but protected from proteolytic degradation by TGF‐β signaling. Furthermore, collagenolytic activity of PSCs‐5d was greatly reduced by TGF‐β1, whereas that of PSCs‐P2 was increased by anti‐RECK antibody. Increased RECK levels were also observed in cerulein‐induced acute pancreatitis. Therefore, our results suggest for the first time proteolytic processing of RECK as a mechanism regulating RECK activity, and demonstrate that TGF‐β signaling in activated PSCs may promote ECM accumulation via a mechanism that preserves the protease inhibitory activity of RECK. J. Cell. Biochem. 104: 1065–1074, 2008. © 2008 Wiley‐Liss, Inc.</description><identifier>ISSN: 0730-2312</identifier><identifier>EISSN: 1097-4644</identifier><identifier>DOI: 10.1002/jcb.21692</identifier><identifier>PMID: 18300271</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Animals ; Cells, Cultured ; Collagen - chemistry ; fibrosis ; Gene Expression Regulation ; GPI-Linked Proteins ; Male ; Matrix Metalloproteinases - metabolism ; Membrane Glycoproteins - biosynthesis ; Membrane Glycoproteins - chemistry ; Membrane Glycoproteins - metabolism ; Membrane Glycoproteins - physiology ; Models, Biological ; Pancreas - cytology ; pancreatic stellate cells ; Pepstatins - pharmacology ; Rats ; Rats, Sprague-Dawley ; RECK ; Signal Transduction ; TGF-β ; Transforming Growth Factor beta - metabolism ; Transforming Growth Factor beta1 - metabolism ; Tumor Suppressor Proteins - biosynthesis ; Tumor Suppressor Proteins - chemistry</subject><ispartof>Journal of cellular biochemistry, 2008-06, Vol.104 (3), p.1065-1074</ispartof><rights>Copyright © 2008 Wiley‐Liss, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3612-b288e2e8f89a33a46352e7d053d4b02d80f8a611fa76e5f5f24eee16f36e9a2a3</citedby><cites>FETCH-LOGICAL-c3612-b288e2e8f89a33a46352e7d053d4b02d80f8a611fa76e5f5f24eee16f36e9a2a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcb.21692$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcb.21692$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18300271$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Hongsik</creatorcontrib><creatorcontrib>Lim, Chaeseung</creatorcontrib><creatorcontrib>Lee, Jungeun</creatorcontrib><creatorcontrib>Kim, Nayoung</creatorcontrib><creatorcontrib>Bang, Sangsu</creatorcontrib><creatorcontrib>Lee, Hojae</creatorcontrib><creatorcontrib>Min, Bonhong</creatorcontrib><creatorcontrib>Park, Gilhong</creatorcontrib><creatorcontrib>Noda, Makoto</creatorcontrib><creatorcontrib>Stetler-Stevenson, William G.</creatorcontrib><creatorcontrib>Oh, Junseo</creatorcontrib><title>TGF-β signaling preserves RECK expression in activated pancreatic stellate cells</title><title>Journal of cellular biochemistry</title><addtitle>J. Cell. Biochem</addtitle><description>Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis, but the detailed mechanism for dysregulated accumulation of extracellular matrix (ECM) remains unclear. Cultured rat PSCs become activated by profibrogenic mediators, but these mediators failed to alter the expression levels of matrix metalloproteinases (MMPs) to the endogenous tissue inhibitors of metalloproteinases (TIMPs). Here, we examined the expression of RECK, a novel membrane‐anchored MMP inhibitor, in PSCs. Although RECK mRNA levels were largely unchanged, RECK protein expression was barely detected at 2, 5 days after plating PSCs, but appeared following continued in vitro culture and cell passage which result in PSC activation. When PSCs at 5 days after plating (PSCs‐5d) were treated with pepstatin A, an aspartic protease inhibitor, or TGF‐β1, a profibrogenic mediator, RECK protein was detected in whole cell lysates. Conversely, Smad7 overexpression or suppression of Smad3 expression in PSCs after passage 2 (PSCs‐P2) led to the loss of RECK protein expression. These findings suggest that RECK is post‐translationally processed in pre‐activated PSCs but protected from proteolytic degradation by TGF‐β signaling. Furthermore, collagenolytic activity of PSCs‐5d was greatly reduced by TGF‐β1, whereas that of PSCs‐P2 was increased by anti‐RECK antibody. Increased RECK levels were also observed in cerulein‐induced acute pancreatitis. Therefore, our results suggest for the first time proteolytic processing of RECK as a mechanism regulating RECK activity, and demonstrate that TGF‐β signaling in activated PSCs may promote ECM accumulation via a mechanism that preserves the protease inhibitory activity of RECK. J. Cell. Biochem. 104: 1065–1074, 2008. © 2008 Wiley‐Liss, Inc.</description><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Collagen - chemistry</subject><subject>fibrosis</subject><subject>Gene Expression Regulation</subject><subject>GPI-Linked Proteins</subject><subject>Male</subject><subject>Matrix Metalloproteinases - metabolism</subject><subject>Membrane Glycoproteins - biosynthesis</subject><subject>Membrane Glycoproteins - chemistry</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Membrane Glycoproteins - physiology</subject><subject>Models, Biological</subject><subject>Pancreas - cytology</subject><subject>pancreatic stellate cells</subject><subject>Pepstatins - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>RECK</subject><subject>Signal Transduction</subject><subject>TGF-β</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Tumor Suppressor Proteins - biosynthesis</subject><subject>Tumor Suppressor Proteins - chemistry</subject><issn>0730-2312</issn><issn>1097-4644</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kM1OwkAUhSdGI4gufAEzKxMXhflpZ9qlNoA_qNGgJG4mQ3tLBkvBmYLwWj6Iz2QR1JWrm5x85-TmQ-iYkiYlhLXGybDJqIjYDqpTEknPF76_i-pEcuIxTlkNHTg3JoREEWf7qEZDXvUkraOHfrfjfX5gZ0aFzk0xwjMLDuwCHH5sxzcYluvAmWmBTYF1UpqFLiHFM10kFnRpEuxKyPMqxEl13SHay3Tu4Gh7G-ip0-7Hl17vvnsVn_e8hAvKvCELQ2AQZmGkOde-4AEDmZKAp_6QsDQkWagFpZmWAoIsyJgPAFRkXECkmeYNdLrZndnp2xxcqSbGrT_QBUznTkkiA0kiWoFnGzCxU-csZGpmzUTblaJErf2pyp_69lexJ9vR-XAC6R-5FVYBrQ3wbnJY_b-kruOLn0lv0zCVp-VvQ9tXJSSXgRrcdRW57cbR4PlFxfwL5jKJVw</recordid><startdate>20080601</startdate><enddate>20080601</enddate><creator>Lee, Hongsik</creator><creator>Lim, Chaeseung</creator><creator>Lee, Jungeun</creator><creator>Kim, Nayoung</creator><creator>Bang, Sangsu</creator><creator>Lee, Hojae</creator><creator>Min, Bonhong</creator><creator>Park, Gilhong</creator><creator>Noda, Makoto</creator><creator>Stetler-Stevenson, William G.</creator><creator>Oh, Junseo</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20080601</creationdate><title>TGF-β signaling preserves RECK expression in activated pancreatic stellate cells</title><author>Lee, Hongsik ; Lim, Chaeseung ; Lee, Jungeun ; Kim, Nayoung ; Bang, Sangsu ; Lee, Hojae ; Min, Bonhong ; Park, Gilhong ; Noda, Makoto ; Stetler-Stevenson, William G. ; Oh, Junseo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3612-b288e2e8f89a33a46352e7d053d4b02d80f8a611fa76e5f5f24eee16f36e9a2a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Collagen - chemistry</topic><topic>fibrosis</topic><topic>Gene Expression Regulation</topic><topic>GPI-Linked Proteins</topic><topic>Male</topic><topic>Matrix Metalloproteinases - metabolism</topic><topic>Membrane Glycoproteins - biosynthesis</topic><topic>Membrane Glycoproteins - chemistry</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Membrane Glycoproteins - physiology</topic><topic>Models, Biological</topic><topic>Pancreas - cytology</topic><topic>pancreatic stellate cells</topic><topic>Pepstatins - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>RECK</topic><topic>Signal Transduction</topic><topic>TGF-β</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Tumor Suppressor Proteins - biosynthesis</topic><topic>Tumor Suppressor Proteins - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Hongsik</creatorcontrib><creatorcontrib>Lim, Chaeseung</creatorcontrib><creatorcontrib>Lee, Jungeun</creatorcontrib><creatorcontrib>Kim, Nayoung</creatorcontrib><creatorcontrib>Bang, Sangsu</creatorcontrib><creatorcontrib>Lee, Hojae</creatorcontrib><creatorcontrib>Min, Bonhong</creatorcontrib><creatorcontrib>Park, Gilhong</creatorcontrib><creatorcontrib>Noda, Makoto</creatorcontrib><creatorcontrib>Stetler-Stevenson, William G.</creatorcontrib><creatorcontrib>Oh, Junseo</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of cellular biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Hongsik</au><au>Lim, Chaeseung</au><au>Lee, Jungeun</au><au>Kim, Nayoung</au><au>Bang, Sangsu</au><au>Lee, Hojae</au><au>Min, Bonhong</au><au>Park, Gilhong</au><au>Noda, Makoto</au><au>Stetler-Stevenson, William G.</au><au>Oh, Junseo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TGF-β signaling preserves RECK expression in activated pancreatic stellate cells</atitle><jtitle>Journal of cellular biochemistry</jtitle><addtitle>J. Cell. Biochem</addtitle><date>2008-06-01</date><risdate>2008</risdate><volume>104</volume><issue>3</issue><spage>1065</spage><epage>1074</epage><pages>1065-1074</pages><issn>0730-2312</issn><eissn>1097-4644</eissn><abstract>Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis, but the detailed mechanism for dysregulated accumulation of extracellular matrix (ECM) remains unclear. Cultured rat PSCs become activated by profibrogenic mediators, but these mediators failed to alter the expression levels of matrix metalloproteinases (MMPs) to the endogenous tissue inhibitors of metalloproteinases (TIMPs). Here, we examined the expression of RECK, a novel membrane‐anchored MMP inhibitor, in PSCs. Although RECK mRNA levels were largely unchanged, RECK protein expression was barely detected at 2, 5 days after plating PSCs, but appeared following continued in vitro culture and cell passage which result in PSC activation. When PSCs at 5 days after plating (PSCs‐5d) were treated with pepstatin A, an aspartic protease inhibitor, or TGF‐β1, a profibrogenic mediator, RECK protein was detected in whole cell lysates. Conversely, Smad7 overexpression or suppression of Smad3 expression in PSCs after passage 2 (PSCs‐P2) led to the loss of RECK protein expression. These findings suggest that RECK is post‐translationally processed in pre‐activated PSCs but protected from proteolytic degradation by TGF‐β signaling. Furthermore, collagenolytic activity of PSCs‐5d was greatly reduced by TGF‐β1, whereas that of PSCs‐P2 was increased by anti‐RECK antibody. Increased RECK levels were also observed in cerulein‐induced acute pancreatitis. Therefore, our results suggest for the first time proteolytic processing of RECK as a mechanism regulating RECK activity, and demonstrate that TGF‐β signaling in activated PSCs may promote ECM accumulation via a mechanism that preserves the protease inhibitory activity of RECK. J. Cell. Biochem. 104: 1065–1074, 2008. © 2008 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>18300271</pmid><doi>10.1002/jcb.21692</doi><tpages>10</tpages></addata></record> |
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subjects | Animals Cells, Cultured Collagen - chemistry fibrosis Gene Expression Regulation GPI-Linked Proteins Male Matrix Metalloproteinases - metabolism Membrane Glycoproteins - biosynthesis Membrane Glycoproteins - chemistry Membrane Glycoproteins - metabolism Membrane Glycoproteins - physiology Models, Biological Pancreas - cytology pancreatic stellate cells Pepstatins - pharmacology Rats Rats, Sprague-Dawley RECK Signal Transduction TGF-β Transforming Growth Factor beta - metabolism Transforming Growth Factor beta1 - metabolism Tumor Suppressor Proteins - biosynthesis Tumor Suppressor Proteins - chemistry |
title | TGF-β signaling preserves RECK expression in activated pancreatic stellate cells |
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