Curcumin inhibits connective tissue growth factor gene expression in activated hepatic stellate cells in vitro by blocking NF‐κB and ERK signalling

Background and purpose: Gene expression of connective tissue growth factor (CTGF) is induced in activated hepatic stellate cells (HSC), the major effectors in hepatic fibrosis, and production of extracellular matrix (ECM) is consequently increased. We previously reported that curcumin, the yellow pigment in curry, suppressed ctgf expression, leading to decreased production of ECM by HSC. The purpose of this study is to evaluate signal transduction pathways involved in the curcumin suppression of ctgf expression in HSC. Experimental approaches: Transient transfection assays were performed to evaluate effects of activation of signalling pathways on the ctgf promoter activity. Real‐time PCR and Western blotting analyses were conducted to determine expression of genes. Results: Suppression of ctgf expression by curcumin was dose‐dependently reversed by lipopolysaccharide (LPS), an NF‐κB activator. LPS increased the abundance of CTGF and type I collagen in HSC in vitro . Activation of NF‐κB by dominant active IκB kinase (IKK), or inhibition of NF‐κB by dominant negative IκBα, caused the stimulation, or suppression of the ctgf promoter activity, respectively. Curcumin suppressed gene expression of Toll‐like receptor‐4, leading to the inhibition of NF‐κB. On the other hand, interruption of ERK signalling by inhibitors or dominant negative ERK, like curcumin, reduced NF‐κB activity and in ctgf expression. In contrast, the stimulation of ERK signalling by constitutively active ERK prevented the inhibitory effects of curcumin. Conclusions and implications: These results demonstrate that the interruption of NF‐κB and ERK signalling by curcumin results in the suppression of ctgf expression in activated HSC in vitro . British Journal of Pharmacology (2008) 153 , 557–567; doi: 10.1038/sj.bjp.0707542 ; published online 29 October 2007