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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Bronchi / cytology
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Bronchi / metabolism*
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Cells, Cultured
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Connective Tissue Growth Factor
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DNA-Binding Proteins / metabolism
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Drug Interactions
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Interleukin-1 / pharmacology
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Interleukin-13 / pharmacology
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Interleukin-4 / pharmacology
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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RNA, Messenger / metabolism
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects
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Smad Proteins
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Trans-Activators / metabolism
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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CCN2 protein, human
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DNA-Binding Proteins
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Enzyme Inhibitors
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Interleukin-1
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Interleukin-13
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RNA, Messenger
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Recombinant Proteins
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Smad Proteins
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TGFB1 protein, human
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Trans-Activators
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha
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Connective Tissue Growth Factor
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Interleukin-4
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Phosphatidylinositol 3-Kinases
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases