INDUCTION OF NEUTROPHIL-ATTRACTING CHEMOKINES IN TRANSFORMING RAT HEPATIC STELLATE CELLS

Background & Aims: Hepatic stellate cells (HSCs) play a key role in th e pathogenesis of liver fibrosis. Immigrating leukocytes can potentiat e the progression of liver fibrosis by release of fibrogenic mediators and cytotoxic actions. The inducible production of neutrophil chemota ctic activities in HSCs was investigated to understand the underlying mechanisms responsible for the attraction of leukocytes in the pathoge nesis of liver fibrosis. Methods: Cultured HSCs of different transform ation grades and after transformation to myofibroblasts (MFBs) were st imulated with tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS), respectively. Induced leukocyte chemotactic activities were ev aluated by chemotaxis assays, enzyme-linked immunosorbent assay, and N orthern blot analysis. Results: A transformation grade-dependent diffe rential responsiveness of HSCs and MFBs was observed. TNF-alpha-induci ble production of chemotactic mediators increased substantially with a dvancing transformation. Only transformed MFBs were LPS responsive. Ma crophage inflammatory protein 2 was identified as one of the inducible chemokines. Conclusions: The results suggest that chemokines play an important role in the pathogenesis of liver fibrosis. Proinflammatory cytokines can initiate the production of chemotactic activities. The m ore HSCs are transformed to MFBs, e.g., by chronic injury, the more se nsitive the cells become to LPS, which may lead to a vicious circle of enhanced fibrogenic and chemotactic mediator production.