C-Jun-NH2-terminal kinase mediates expression of connective tissue growth factor induced by transforming growth factor-beta1 in human lung fibroblasts.
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.
Utsugi
Mitsuyoshi
M
First Department of Internal Medicine, Gunma University Faculty of Medicine, School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan. mutsugi@med.gunma-u.ac.jp
Dobashi
Kunio
K
Ishizuka
Tamotsu
T
Masubuchi
Ken
K
Shimizu
Yasuo
Y
Nakazawa
Tsugio
T
Mori
Masatomo
M
D000730:Androstadienes / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000166:cytology; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051899:Smad2 Protein; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D000873:Anthracenes; D002867:Chromones; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C526317:CCN2 protein, human; C497782:SMAD2 protein, human; C508960:TGFB1 protein, human; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580