Pigment epithelium-derived factor (PEDF) blocks the interleukin-6 signaling to C-reactive protein expression in Hep3B cells by suppressing Rac-1 activation

There is a growing body of evidence to show that that C-reactive protein (CRP), an acute phase reactant, is one of the most valuable predictors of future cardiovascular events. Since CRP proteins directly contribute to the development and progression of atherosclerosis as well, reduction of CRP levels maybe a novel therapeutic target for the treatment of cardiovascular disease. In this study, we examined whether pigment epithelium-derived factor (PEDF) could block the interleukin-6-induced CRP expression in cultured human hepatoma cells and the way that it might achieve this effect. PEDF inhibited the IL-6-induced CRP expression in Hep3B cells at both mRNA and proteins levels. PEDF suppressed the intracellular reactive oxygen species generation in IL-6-exposed Hep3B cells. Anti-oxidants mimicked the effects of PEDF. PEDF was also found to inhibit the IL-6-elicited Rac-1 activation, whereas dominant-negative Rac-1 dose-dependently decreased the CRP mRNA levels. PEDF blocked the IL-6-induced STAT3 phosphorylations and NF-kappa B p65 activity in Hep3B cells. Our present study suggests that PEDF could be one of the potent suppressors of CRP production by the liver and may play a protective role against atherosclerosis. (c) 2006 Elsevier Inc. All rights reserved.