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HIGHLIGHT Volume 317, Issue 7, April 15, 2011 Tumor necrosis factor a stimulates endothelin-1 synthesis in rat hepatic stellate cells in hepatic wound healing through a novel IKK/JNK pathway. By Shuxin Zhan and Don C. Rockey . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 Endothelin-1(ET-1), a potent vasoconstrictor up-regulated during wound-healing, stimulates several functions in myofibroblasts (hepatic stellate cells in liver). Thus, we explored the ability of tumor necrosis factor alpha(TNFa), an inflammatory cytokine, to regulate ET-1 synthesis in stellate cells. We show that TNFa induces ET-1 transcription and production through the IKK signaling pathway(also important in inflammation). We also demonstrate that the IKK complex induces activation not only of ERK as has been previously reported, but additionally of JNK(then c-Jun), to stimulate preproET-1 transcription. This latter pathway is entirely novel. Finally, TNFa caused ET1 mediated stellate cell contraction. The work emphasizes the functional importance of TNFa mediated ET-1 synthesis through a novel signaling pathway, and has important implications for liver wound-healing.