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JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human

Tzu-Yu Hou1,2,3, Shi-Bei Wu4, Hui-Chuan Kau1,2,3,5

  • 1Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, Taiwan.

International Journal of Molecular Sciences
|April 3, 2021
PubMed

Insights

Transforming growth factor-β1 (TGF-β1) activates Graves

Area of Science:

  • Ophthalmology
  • Cell Biology
  • Molecular Biology

Background:

  • Graves' ophthalmopathy (GO) involves tissue remodeling and fibrosis driven by transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation.
  • The precise signaling pathways mediating TGF-β1 activation of orbital fibroblasts in GO are not fully understood.

Purpose of the Study:

  • To investigate the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves' orbital fibroblasts.

Main Methods:

  • Western blots were used to measure the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK).
  • Expression of fibrogenic markers (CTGF, α-SMA, fibronectin) and extracellular matrix (ECM) regulators (MMPs, TIMPs) was analyzed.
  • Pharmacologic kinase inhibitors targeting the MAPK pathway were employed to validate findings.

Main Results:

  • TGF-β1 treatment increased phosphorylation of p38 and JNK, but not ERK.
  • Fibrogenic markers (CTGF, α-SMA, fibronectin) and TIMP-1/TIMP-3 were upregulated, while MMP-2/-9 activity decreased.
  • Inhibition of p38 and JNK pathways abolished TGF-β1-induced changes in marker expression.

Conclusions:

  • TGF-β1 induces myofibroblast transdifferentiation in human Graves' orbital fibroblasts.
  • The p38 and JNK signaling pathways are critical mediators of this TGF-β1-induced process.
Keywords:
Graves’ ophthalmopathyGraves’ orbital fibroblastsc-Jun N-terminal kinasemitogen-activated protein kinasep38transforming growth factor-β1

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