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C-Jun-NH₂-Terminal Kinase Mediates Expression of Connective Tissue Growth Factor Induced by Transforming Growth Factor-ß1 in Human Lung Fibroblasts

First Department of Internal Medicine, Gunma University Faculty of Medicine, School of Medicine; and Gunma University Faculty of Health Sciences, Maebashi, Japan

Address correspondence to: Mitsuyoshi Utsugi, M.D., Ph.D., First Department of Internal Medicine, Gunma University Faculty of Medicine, School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan. E-mail: mutsugi{at}med.gunma-u.ac.jp

Many of the fibrogenic effects of transforming growth factor-ß (TGF-ß) 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-ß1 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-ß1–induced CTGF expression. On the other hand, specific inhibitors of phosphatidylinositol 3-kinase (PI3K) suppressed TGF-ß1–induced CTGF expression in a concentration-dependent manner. TGF-ß1 activated c-Jun NH₂-terminal kinase (JNK) and p38 MAP kinase, but not ERK in HFL-1 cells. PI3K inhibitors dose-dependently suppressed TGF-ß1–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-ß1–induced CTGF expression. These results suggest that TGF-ß1–induced CTGF mRNA expression is mediated through the JNK-dependent pathway, whereas p38 MAP kinase and ERK pathways minimally contribute.

Abbreviations: connective tissue growth factor, CTGF • dimethyl sulfoxide, DMSO • extracellular signal–regulated kinase, ERK • fetal bovine serum, FBS • glyceraldehyde-3-phosphate dehydrogenase, G3PDH • human fetal lung fibroblasts, HFL-1 • c-Jun NH₂-terminal kinase, JNK • mitogen-activated protein kinase, MAP kinase • MAP kinase-activated protein kinase, MAPKAPK • mitogen-activated protein kinase kinase, MEK • polymerase chain reaction, PCR • phosphatidylinositol 3-kinase, PI3K • transforming growth factor-ß, TGF-ß

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