Abstract
Many of the fibrogenic effects of transforming growth factor-beta (TGF-beta) might be mediated by connective tissue growth factor (CTGF). The present study investigates the role of mitogen-activated protein (MAP) kinase in the expression of CTGF mRNA in the human lung fibroblast line, HFL-1. TGF-beta1 enhanced CTGF mRNA levels in a time- and concentration-dependent manner, and this enhancement was also dependent upon transcription. Inhibition of p38 MAP kinase or extracellular signal-regulated kinase (ERK) activation did not affect TGF-beta1-induced CTGF expression. On the other hand, specific inhibitors of phosphatidylinositol 3-kinase (PI3K) suppressed TGF-beta1-induced CTGF expression in a concentration-dependent manner. TGF-beta1 activated c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not ERK in HFL-1 cells. PI3K inhibitors dose-dependently suppressed TGF-beta1-induced JNK, but not p38 MAP kinase activation. Finally, JNK1 and JNK2 antisense oligonucleotides attenuated cellular levels of JNK1 and JNK2 protein, respectively, and repressed TGF-beta1-induced CTGF expression. These results suggest that TGF-beta1-induced CTGF mRNA expression is mediated through the JNK-dependent pathway, whereas p38 MAP kinase and ERK pathways minimally contribute.
MeSH terms
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Androstadienes / pharmacology
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Anthracenes / pharmacology
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Cells, Cultured
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Chromones / pharmacology
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Connective Tissue Growth Factor
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / metabolism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Gene Expression Regulation / drug effects*
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Humans
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Imidazoles / pharmacology
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Immediate-Early Proteins / drug effects
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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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JNK Mitogen-Activated Protein Kinases
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Lung / cytology
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Morpholines / pharmacology
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Oligonucleotides, Antisense / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Pyridines / pharmacology
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Smad2 Protein
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Trans-Activators / drug effects
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Trans-Activators / metabolism
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
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Wortmannin
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p38 Mitogen-Activated Protein Kinases
Substances
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Androstadienes
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Anthracenes
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CCN2 protein, human
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Chromones
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DNA-Binding Proteins
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Enzyme Inhibitors
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Imidazoles
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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Morpholines
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Oligonucleotides, Antisense
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Phosphoinositide-3 Kinase Inhibitors
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Pyridines
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RNA, Messenger
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SMAD2 protein, human
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Smad2 Protein
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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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Connective Tissue Growth Factor
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pyrazolanthrone
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Mitogen-Activated Protein Kinase 9
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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SB 203580
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Wortmannin