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JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts
Authors:Tzu-Yu Hou  Shi-Bei Wu  Hui-Chuan Kau  Chieh-Chih Tsai
Affiliation:1.Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, Taiwan; (T.-Y.H.); (H.-C.K.);2.School of Medicine, National Yang Ming University, Taipei 112, Taiwan;3.School of Medicine, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan;4.Biomedical Commercialization Center, Taipei Medical University, Taipei 110, Taiwan;5.Department of Ophthalmology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei 112, Taiwan
Abstract:Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.
Keywords:c-Jun N-terminal kinase  Graves’  orbital fibroblasts  Graves’  ophthalmopathy  mitogen-activated protein kinase  p38  transforming growth factor-β  1
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