Suppression of hepatocyte growth factor induction by interleukin 1 and its role in the termination of liver regeneration

点击翻译按钮获取中文摘要

HGF production in cultured human dermal fibroblasts is induced by PKA-activating agents such as 8-bromo-cAMP and cholera toxin, phorbol esters such as TPA, and growth factors such as EGF. HGF production in various types of cells is also stimulated by IL-1 and TNF-α. When we examined combined effects of HGF inducers, we unexpectedly found that IL-1 strongly inhibited the induction of HGF. In this study, this inhibition was characterized. HGF production in human dermal fibroblasts was induced only slightly by IL-1 α IL-1 β and TNF-α. However, IL-1 α, IL-1β and TNF-α strongly inhibited 8-bromo-cAMP- and cholera toxin-induced HGF production. Maximal inhibitions by IL-1 and TNF-α were observed at 100 pg/mL and 3 JRU/mL, respectively. The inhibitory effects of IL-1 and TNF-α were larger than that of dexamethasone and were as large as or larger than that of TGF-β. The inhibitory effects of IL-1 and TNF-α were detected at and offer 48 h of incubation. Results of Northern blot analysis showed t … More hat both IL-1 and TNF-α inhibited the up-regulation of HGF gene expression induced by cholera toxin. The inhibitory effect of IL-1 was diminished by the IL-1 receptor antagonist. HGF inductions by EGF and TPA were also suppressed by IL-1. The inhibitory effect of IL-1 on EGF-induced HGF production was smaller than that of TGF-β but larger than those of dexamethasone and rethoic acid. The signal of IL-1 is transmitted through the MAPK family cascade and the IKK cascade. The inhibitory effect of IL-1 was not diminished by NF-kB inhibitors but diminished partially by the inhibitor of either p38 or MEK and significantly by the combination of both inhibitors, suggesting that the activation of p38 and MEK-MAPK but not the activation of NF-kB is at least partly involved in the inhibitory effect of IL-1. Since IL-1 inhibits DNA synthesis in adult rat hepatocytes in primary culture, it is possible that IL-1 acts as a dual inhibitor of DNA synthesis in liver regeneration: it not only directly inhibits DNA synthesis of hepatocytes, but also suppresses production of HGF. Less