Regulation of TGF-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells
Transforming growth factor (TGF)-beta may play an important role in airway remodeling, and the fibrogenic effect of TGF-beta may be mediated through connective tissue growth factor (CTGF) release. We investigated the role of MAPKs and phosphatidylinositol 3-kinase (PI3K) and the effects of inflammat...
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Veröffentlicht in: | American journal of physiology. Lung cellular and molecular physiology 2005-01, Vol.288 (1), p.L68 |
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creator | Xie, Shaoping Sukkar, Maria B Issa, Razao Oltmanns, Ute Nicholson, Andrew G Chung, Kian Fan |
description | Transforming growth factor (TGF)-beta may play an important role in airway remodeling, and the fibrogenic effect of TGF-beta may be mediated through connective tissue growth factor (CTGF) release. We investigated the role of MAPKs and phosphatidylinositol 3-kinase (PI3K) and the effects of inflammatory cytokines on TGF-beta-induced CTGF expression in human airway smooth muscle cells (ASMC). We examined whether Smad signal was involved in the regulatory mechanisms. TGF-beta 1 induced a time- and concentration-dependent expression of CTGF gene and protein as analyzed by real-time RT-PCR and Western blot. Inhibition of ERK and c-jun NH(2)-terminal kinase (JNK), but not of p38 MAPK and PI3K, blocked the effect of TGF-beta 1 on CTGF mRNA and protein expression and on Smad2/3 phosphorylation. T helper lymphocyte 2-derived cytokines, IL-4 and IL-13, attenuated TGF-beta 1-stimulated mRNA and protein expression of CTGF and inhibited TGF-beta 1-stimulated ERK1/2 and Smad2/3 activation in ASMC. The proinflammatory cytokines tumor necrosis factor-alpha and IL-1 beta reduced TGF-beta 1-stimulated mRNA expression of CTGF but did not inhibit TGF-beta-induced Smad2/3 phosphorylation. TGF-beta 1-stimulated CTGF expression is mediated by mechanisms involving ERK and JNK pathways and is downregulated by IL-4 and IL-13 through modulation of Smad and ERK signals. |
doi_str_mv | 10.1152/ajplung.00156.2004 |
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We investigated the role of MAPKs and phosphatidylinositol 3-kinase (PI3K) and the effects of inflammatory cytokines on TGF-beta-induced CTGF expression in human airway smooth muscle cells (ASMC). We examined whether Smad signal was involved in the regulatory mechanisms. TGF-beta 1 induced a time- and concentration-dependent expression of CTGF gene and protein as analyzed by real-time RT-PCR and Western blot. Inhibition of ERK and c-jun NH(2)-terminal kinase (JNK), but not of p38 MAPK and PI3K, blocked the effect of TGF-beta 1 on CTGF mRNA and protein expression and on Smad2/3 phosphorylation. T helper lymphocyte 2-derived cytokines, IL-4 and IL-13, attenuated TGF-beta 1-stimulated mRNA and protein expression of CTGF and inhibited TGF-beta 1-stimulated ERK1/2 and Smad2/3 activation in ASMC. The proinflammatory cytokines tumor necrosis factor-alpha and IL-1 beta reduced TGF-beta 1-stimulated mRNA expression of CTGF but did not inhibit TGF-beta-induced Smad2/3 phosphorylation. TGF-beta 1-stimulated CTGF expression is mediated by mechanisms involving ERK and JNK pathways and is downregulated by IL-4 and IL-13 through modulation of Smad and ERK signals.</description><identifier>ISSN: 1040-0605</identifier><identifier>DOI: 10.1152/ajplung.00156.2004</identifier><identifier>PMID: 15377500</identifier><language>eng</language><publisher>United States</publisher><subject>Bronchi - cytology ; Bronchi - metabolism ; Cells, Cultured ; Connective Tissue Growth Factor ; DNA-Binding Proteins - metabolism ; Drug Interactions ; Enzyme Activation ; Enzyme Inhibitors - pharmacology ; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Humans ; Immediate-Early Proteins - genetics ; Immediate-Early Proteins - metabolism ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Interleukin-1 - pharmacology ; Interleukin-13 - pharmacology ; Interleukin-4 - pharmacology ; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinases - metabolism ; Myocytes, Smooth Muscle - cytology ; Myocytes, Smooth Muscle - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; Recombinant Proteins - pharmacology ; RNA, Messenger - metabolism ; Signal Transduction - drug effects ; Smad Proteins ; Trans-Activators - metabolism ; Transforming Growth Factor beta - pharmacology ; Transforming Growth Factor beta1 ; Tumor Necrosis Factor-alpha - pharmacology</subject><ispartof>American journal of physiology. 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Lung cellular and molecular physiology</title><addtitle>Am J Physiol Lung Cell Mol Physiol</addtitle><description>Transforming growth factor (TGF)-beta may play an important role in airway remodeling, and the fibrogenic effect of TGF-beta may be mediated through connective tissue growth factor (CTGF) release. We investigated the role of MAPKs and phosphatidylinositol 3-kinase (PI3K) and the effects of inflammatory cytokines on TGF-beta-induced CTGF expression in human airway smooth muscle cells (ASMC). We examined whether Smad signal was involved in the regulatory mechanisms. TGF-beta 1 induced a time- and concentration-dependent expression of CTGF gene and protein as analyzed by real-time RT-PCR and Western blot. Inhibition of ERK and c-jun NH(2)-terminal kinase (JNK), but not of p38 MAPK and PI3K, blocked the effect of TGF-beta 1 on CTGF mRNA and protein expression and on Smad2/3 phosphorylation. T helper lymphocyte 2-derived cytokines, IL-4 and IL-13, attenuated TGF-beta 1-stimulated mRNA and protein expression of CTGF and inhibited TGF-beta 1-stimulated ERK1/2 and Smad2/3 activation in ASMC. The proinflammatory cytokines tumor necrosis factor-alpha and IL-1 beta reduced TGF-beta 1-stimulated mRNA expression of CTGF but did not inhibit TGF-beta-induced Smad2/3 phosphorylation. TGF-beta 1-stimulated CTGF expression is mediated by mechanisms involving ERK and JNK pathways and is downregulated by IL-4 and IL-13 through modulation of Smad and ERK signals.</description><subject>Bronchi - cytology</subject><subject>Bronchi - metabolism</subject><subject>Cells, Cultured</subject><subject>Connective Tissue Growth Factor</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Interactions</subject><subject>Enzyme Activation</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Humans</subject><subject>Immediate-Early Proteins - genetics</subject><subject>Immediate-Early Proteins - metabolism</subject><subject>Intercellular Signaling Peptides and Proteins - genetics</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Interleukin-1 - pharmacology</subject><subject>Interleukin-13 - pharmacology</subject><subject>Interleukin-4 - pharmacology</subject><subject>JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Myocytes, Smooth Muscle - cytology</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Recombinant Proteins - pharmacology</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Smad Proteins</subject><subject>Trans-Activators - metabolism</subject><subject>Transforming Growth Factor beta - pharmacology</subject><subject>Transforming Growth Factor beta1</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><issn>1040-0605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1j9FKwzAYRnOhuDl9AS8kL9D6p2nS9FKGm8JAkHk90uRvzWib0qTOvb0V9eo7Fx8HDiF3DFLGRPagj0M79U0KwIRMM4D8giwZ5JCABLEg1yEcAUAAyCuyYIIXxcxL4t6wmVodne-pr-l-u0kqjJqyxPV2Mmip8X2PJrpPpNGFMCFtRn-KH7TWJvqR4tcwYgg_AtdT7caTPtPQeT9fuimYFqnBtg035LLWbcDbv12R983Tfv2c7F63L-vHXTIwXsZEKSiY1EoprqzJygxyJjOsK2vLORRlAZZZAYh5pmRZVYZLLgSUABwrYfiK3P96h6nq0B6G0XV6PB_-m_k3A7BZNg</recordid><startdate>200501</startdate><enddate>200501</enddate><creator>Xie, Shaoping</creator><creator>Sukkar, Maria B</creator><creator>Issa, Razao</creator><creator>Oltmanns, Ute</creator><creator>Nicholson, Andrew G</creator><creator>Chung, Kian Fan</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>200501</creationdate><title>Regulation of TGF-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells</title><author>Xie, Shaoping ; Sukkar, Maria B ; Issa, Razao ; Oltmanns, Ute ; Nicholson, Andrew G ; Chung, Kian Fan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p139t-880716a88838dc29204162efbdd9152e670d1d50ee42869bbc3635509003eb5c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Bronchi - cytology</topic><topic>Bronchi - metabolism</topic><topic>Cells, Cultured</topic><topic>Connective Tissue Growth Factor</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug Interactions</topic><topic>Enzyme Activation</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Humans</topic><topic>Immediate-Early Proteins - genetics</topic><topic>Immediate-Early Proteins - metabolism</topic><topic>Intercellular Signaling Peptides and Proteins - genetics</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Interleukin-1 - pharmacology</topic><topic>Interleukin-13 - pharmacology</topic><topic>Interleukin-4 - pharmacology</topic><topic>JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Myocytes, Smooth Muscle - cytology</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Recombinant Proteins - pharmacology</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Smad Proteins</topic><topic>Trans-Activators - metabolism</topic><topic>Transforming Growth Factor beta - pharmacology</topic><topic>Transforming Growth Factor beta1</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xie, Shaoping</creatorcontrib><creatorcontrib>Sukkar, Maria B</creatorcontrib><creatorcontrib>Issa, Razao</creatorcontrib><creatorcontrib>Oltmanns, Ute</creatorcontrib><creatorcontrib>Nicholson, Andrew G</creatorcontrib><creatorcontrib>Chung, Kian Fan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>American journal of physiology. Lung cellular and molecular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xie, Shaoping</au><au>Sukkar, Maria B</au><au>Issa, Razao</au><au>Oltmanns, Ute</au><au>Nicholson, Andrew G</au><au>Chung, Kian Fan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of TGF-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells</atitle><jtitle>American journal of physiology. Lung cellular and molecular physiology</jtitle><addtitle>Am J Physiol Lung Cell Mol Physiol</addtitle><date>2005-01</date><risdate>2005</risdate><volume>288</volume><issue>1</issue><spage>L68</spage><pages>L68-</pages><issn>1040-0605</issn><abstract>Transforming growth factor (TGF)-beta may play an important role in airway remodeling, and the fibrogenic effect of TGF-beta may be mediated through connective tissue growth factor (CTGF) release. We investigated the role of MAPKs and phosphatidylinositol 3-kinase (PI3K) and the effects of inflammatory cytokines on TGF-beta-induced CTGF expression in human airway smooth muscle cells (ASMC). We examined whether Smad signal was involved in the regulatory mechanisms. TGF-beta 1 induced a time- and concentration-dependent expression of CTGF gene and protein as analyzed by real-time RT-PCR and Western blot. Inhibition of ERK and c-jun NH(2)-terminal kinase (JNK), but not of p38 MAPK and PI3K, blocked the effect of TGF-beta 1 on CTGF mRNA and protein expression and on Smad2/3 phosphorylation. T helper lymphocyte 2-derived cytokines, IL-4 and IL-13, attenuated TGF-beta 1-stimulated mRNA and protein expression of CTGF and inhibited TGF-beta 1-stimulated ERK1/2 and Smad2/3 activation in ASMC. The proinflammatory cytokines tumor necrosis factor-alpha and IL-1 beta reduced TGF-beta 1-stimulated mRNA expression of CTGF but did not inhibit TGF-beta-induced Smad2/3 phosphorylation. TGF-beta 1-stimulated CTGF expression is mediated by mechanisms involving ERK and JNK pathways and is downregulated by IL-4 and IL-13 through modulation of Smad and ERK signals.</abstract><cop>United States</cop><pmid>15377500</pmid><doi>10.1152/ajplung.00156.2004</doi></addata></record> |
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subjects | Bronchi - cytology Bronchi - metabolism Cells, Cultured Connective Tissue Growth Factor DNA-Binding Proteins - metabolism Drug Interactions Enzyme Activation Enzyme Inhibitors - pharmacology Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases - metabolism Humans Immediate-Early Proteins - genetics Immediate-Early Proteins - metabolism Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Interleukin-1 - pharmacology Interleukin-13 - pharmacology Interleukin-4 - pharmacology JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - metabolism Myocytes, Smooth Muscle - cytology Myocytes, Smooth Muscle - metabolism Phosphatidylinositol 3-Kinases - metabolism Recombinant Proteins - pharmacology RNA, Messenger - metabolism Signal Transduction - drug effects Smad Proteins Trans-Activators - metabolism Transforming Growth Factor beta - pharmacology Transforming Growth Factor beta1 Tumor Necrosis Factor-alpha - pharmacology |
title | Regulation of TGF-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells |
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