Differential expression of monocyte chemotactic protein-1 (MCP-1) in transforming rat hepatic stellate cells

Backgrounds/Aims: Hepatic stellate cells and infiltrating leukocytes play a key role in the pathogenesis of liver fibrosis. The chronic phase of liver inflammation is characterized by immigrating mononuclear cells. To underst and the underlying mechanisms responsible for the attraction of mononuclear cells in the pathogenesis of liver fibrosis, we investigated the inducible production of chemotactic activities in hepatic stellate cells. Methods: Cultured hepatic stellate cells of different transformation grades and after in vitro transformation to myofibroblast-like cells were stimula ted with tumor necrosis factor-a or bacterial lipopolysaccharide. Mononucle ar cell attracting chemotactic activities mere evaluated by chemotaxis assa ys, ELISA, and Northern blot analysis. Results: We observed a transformation grade-dependent differential responsi veness of hepatic stellate cells and myofibroblast-like cells. Monocyte che motactic protein-1 was inducible by tumor necrosis factor-alpha in non-tran sformed hepatic stellate cells. In contrast, monocyte chemotactic protein-1 was not inducible by bacterial lipopolysaccharide until the cells were ful ly transformed into myofibroblast-like cells. Despite a delayed onset, the bacterial lipopolysaccharide-inducible monocyte chemotactic protein-1 expre ssion did not depend on an endogenous production of tumor necrosis factor-a lpha. Conclusions: Our results indicate that the tumor necrosis factor-alpha and bacterial lipopolysaccharide-inducible production of chemokines plays a cen tral role in the pathogenesis of liver fibrosis, These data suggest that wh en hepatic stellate cells have been transformed to a myofibroblast-like cel ls phenotype, e.g. by chronic injury, the cells become more sensitive to ba cterial lipopolysaccharide, which may potentiate the production of chemotac tic and fibrogenic mediators. A strong secretion of monocyte chemotactic pr otein-1 may contribute to the maintenance of an inflammatory infiltrate dom inated by mononuclear cells.