Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 604, Issue 1-3, Pages 12-19Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2008.12.004
Keywords
Tumor necrosis factor-alpha; DNA synthesis; Proliferation; Signal transduction; Transforming growth factor-alpha; Hepatocyte; (Adult rat)
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We investigated the effects of tumor necrosis factor (TNF)-alpha on DNA synthesis and proliferation, and its signal transduction pathways in primary cultures of adult rat hepatocytes. TNF-alpha induced time- and dose-dependent increases in hepatocyte DNA synthesis and proliferation. The hepatocyte proliferation stimulated by 30 ng/ml TNF-alpha was significantly inhibited by anti-TNF receptor 2 antibody, but not by anti-TNF receptor I antibody. TNF-alpha-induced hepatocyte DNA synthesis and proliferation were blocked by AG1478 (10(-7) M). PD98059 (10(-6) M), LY 294002 (10(-7) M), and rapamycin (100 ng/ml). TNF-alpha at 30 ng/ml significantly increased phosphorylation of receptor tyrosine kinase (175 kDa) and p42 mitogen-activated protein (MAP) kinase. This data suggests that the proliferative signal for primary cultured hepatocytes induced by TNF-alpha is mediated by TNF receptor 2 and the receptor tyrosine kinase/MAP kinase pathway. In addition, TNF-alpha-induced hepatocyte mitogenesis was significantly blocked by somatostatin (10(-6) M), adenylate cyclase inhibitor dideoxyadenosine (10(-7) M), protein kinase A inhibitor H-89 (10(-7) M), and neutralizing antibody to transforming growth factor (TGF)-alpha in culture. Indeed, 30 ng/ml TNF-alpha was found to rapidly stimulate secretion of TGF-alpha, and this secretion was also blocked by anti-TNF receptor 2 antibody. Moreover, TGF-alpha secretion induced by TNF-alpha was suppressed by dideoxyadenosine, H-89, and somatostatin. Together, these results indicate that stimulation of TNF receptor 2 by 30 ng/ml TNF-alpha induces autocrine secretion of TGF-alpha via the adenylate cyclase/protein kinase A pathway, after which TGF-alpha induces hepatocyte DNA synthesis and proliferation through the TGF-alpha receptor-linked tyrosine kinase (175 kDa)/MAP kinase signaling system. (C) 2008 Published by Elsevier B.V.
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