期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 310, 期 2, 页码 520-527出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.104.067280
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In response to pancreatic injury and in cell culture, pancreatic stellate cells (PSCs) are transformed (activated) into highly proliferative myofibroblast-like cells that express alpha-smooth muscle actin and produce extracellular matrix components. Activated PSCs are implicated in the pathogenesis of pancreatic fibrosis and inflammation. We here evaluated the effects of SP600125 ( anthra[1,9-cd] pyrazole-6 (2H)-one), an inhibitor of c-Jun NH2-terminal kinase (JNK), on the activation of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. Activation of JNK was determined by Western blotting using anti-phosphospecific JNK and c-Jun antibodies. Activation of transcription factors was determined by electrophoretic mobility shift assay. The effects of SP600125 on the key parameters of activation ( chemokine production, collagen production, and proliferation) were examined. The effect of SP600125 on the activation of freshly isolated PSCs in culture also was examined. Interleukin-1beta activated both 46- and 54-kDa JNK, whereas platelet-derived growth factor-BB activated only 46- kDa JNK. SP600125 inhibited interleukin-1beta-induced JNK activity and activator protein-1 activation, but it did not affect the activation of extracellular-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-kappaB. SP600125 inhibited platelet-derived growth factor-induced proliferation, inducible monocyte chemoattractant protein-1 production, and serum-induced type I collagen production. Although SP600125 did not inhibit the transformation, it attenuated the proliferation of freshly isolated PSCs in culture. Collectively, our results suggest a role of JNK in the activation of PSCs, and a potential application of JNK inhibitors for the treatment of pancreatic fibrosis and inflammation.
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