The interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPARγ in rat activated hepatic stellate cell in vitro

Activation of hepatic stellate cells ( HSC), the major effector in hepatic fibrogenesis, is coupled with sequential alterations in expression of genes, including the upregulation of platelet-derived growth factor-beta receptor ( PDGF-beta R) and epidermal growth factor receptor ( EGFR), as well as the down-regulation of the peroxisome proliferator-activated receptor-gamma (PPAR gamma). However, the relationship among the alterations in expression of the genes and the activation of their signaling in activated HSC remains obscure. We recently showed that curcumin, the yellow pigment in curry, inhibited cell growth and induced gene expression of endogenous PPAR gamma in activated HSC in vitro. The present study is to elucidate the underlying mechanisms, focusing on the impacts of PDGF and EGF signaling. It is hypothesized that the interruption of the PDGF and EGF signaling pathways by curcumin might stimulate gene expression of PPAR gamma in activated HSC. Our results in this report indicate that the activation of PDGF or EGF signaling by exogenous PDGF or EGF inhibits PPAR gamma gene expression in passaged HSC. Curcumin interrupts PDGF and EGF signaling demonstrated by inhibiting tyrosine phosphorylation of PDGF-beta R and EGFR and by reducing the levels of phosphorylated phosphatidylinositol-3 kinase ( PI-3K/AKT), extracellular signal-regulated kinase ( ERK) and the Jun N-terminal kinase ( JNK). The blockade of PI-3K/AKT, ERK or JNK signaling negatively regulates PPAR gamma gene expression in activated HSC, leading to the reduction in cell growth, including inducing cell arrest and apoptosis. Our results collectively demonstrate that the interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPAR gamma in activated HSC. These results provide novel insights into the mechanisms of curcumin in the induction of PPAR gamma gene expression in activated HSC.