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C-Jun-NH2-terminal kinase mediates expression of connective tissue growth factor induced by transforming growth

Mitsuyoshi Utsugi1, Kunio Dobashi, Tamotsu Ishizuka

  • 1First 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

American Journal of Respiratory Cell and Molecular Biology
|May 23, 2003
PubMed

Insights

Transforming growth factor-beta (TGF-beta) stimulates connective tissue growth factor (CTGF) mRNA expression in lung fibroblasts. This process primarily involves the c-Jun NH2-terminal kinase (JNK) pathway, not p38 MAP kinase or ERK.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-beta) is implicated in fibrotic diseases.
  • Connective tissue growth factor (CTGF) is a key mediator of TGF-beta's fibrogenic effects.
  • Understanding the signaling pathways involved in CTGF expression is crucial for developing anti-fibrotic therapies.

Purpose of the Study:

  • To investigate the role of mitogen-activated protein (MAP) kinase pathways in TGF-beta1-induced CTGF mRNA expression in human lung fibroblasts (HFL-1).
  • To elucidate the specific signaling molecules and pathways mediating CTGF regulation by TGF-beta1.

Main Methods:

  • Human lung fibroblast cell line (HFL-1) was treated with TGF-beta1.
  • Investigated CTGF mRNA expression using quantitative methods.
  • Utilized specific inhibitors for p38 MAP kinase, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K).
  • Assessed activation of JNK, p38 MAP kinase, and ERK signaling pathways.
  • Employed antisense oligonucleotides for JNK1 and JNK2.

Main Results:

  • TGF-beta1 significantly increased CTGF mRNA levels in a time- and concentration-dependent manner, requiring transcription.
  • Inhibition of p38 MAP kinase and ERK did not affect TGF-beta1-induced CTGF expression.
  • Specific PI3K inhibitors suppressed TGF-beta1-induced CTGF expression and JNK activation.
  • TGF-beta1 activated JNK and p38 MAP kinase, but not ERK.
  • JNK1 and JNK2 antisense oligonucleotides reduced CTGF expression.

Conclusions:

  • TGF-beta1-induced CTGF mRNA expression in HFL-1 cells is primarily mediated by the JNK signaling pathway.
  • The p38 MAP kinase and ERK pathways play minimal roles in this process.
  • PI3K acts upstream of JNK activation in the TGF-beta1 signaling cascade leading to CTGF expression.

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