Inhibition of hepatocyte growth factor induction in human dermal fibroblasts by interleukin-1 and its prevention by interferon-γ

Abstract

Hepatocyte growth factor (HGF) is one of the vital factors for liver regeneration. HGF production is induced by the activation of protein kinase A and protein kinase C-mediated pathways, interleukin (IL)-1, tumor necrosis factor (TNF)-α, and epidermal growth factor (EGF) in mesenchymal cells. We here report that IL-1 and TNF-α, hitherto regarded as HGF inducers, potently inhibited HGF production stimulated by other HGF inducers. IL-1α, IL-1β, and TNF-α alone had minimal stimulating effects on HGF production in human dermal fibroblasts, but they strongly inhibited production of HGF induced by cholera toxin, 8-bromo-cAMP, EGF, and phorbol 12-myristate 13-acetate (PMA). Moreover, although the high level of HGF production in MRC-5 cells was enhanced by PMA and less markedly by IL-1β, HGF production in MRC-5 cells treated with PMA plus IL-1β was less than that in the cells treated with PMA alone. In the presence of interferon (IFN)-γ, however, cholera toxin- and 8-bromo-cAMP-induced HGF production was not inhibited by IL-1β. Pretreatment of cells with IL-1β suppressed the phosphorylation of cAMP-responsive element-binding protein induced by cholera toxin but not that induced by 8-bromo-cAMP. Taken together, our results indicate that IL-1 inhibited HGF production stimulated by various inducers, including protein kinase A-activating agents, and that IFN-γ overcame this inhibition of induction of HGF production.