Macrophage inflammatory protein-1α shows profibrotic effects in two experimental liver fibosis

Abstract

Background and Aims: Liver fibrosis is associated with infiltrating immune cells and activation of hepatic stellate cells which leads to excess production of extracellular matrix proteins. We here aimed to investigate the effects of the CC chemokine CCL3, also known as macrophage inflammatory protein-1α (MIP-1α), in two different fibrosis models. Methods: We treated mice with either CCl4 or with a MCD diet to induce fibrosis in CCL3 deficient (CCL3 -/-) and wild-type mice. Fibrosis was analyzed by histology (sirius red staining), hydroxyproline content and intrahepatic mRNA expression of fibrosis-related genes (Col1a1, Timp1, Mmp2 and α-Sma) in liver samples. In vitro, the effects of CCL3 on the proliferation (BrdU assay, Scratch assay) were evaluated in cell culture. Results: In this study, we show that the protein expression of CCL3 is increased in wild-type mice after chronic liver injury (P<0.05). Accordingly, CCL3 -/- mice are protected from liver fibrosis compared to their wild-type counterparts what was shown by histological staining and biochemically (P<0.05). We could validate these results by treating the two mouse groups with either carbon tetrachloride (CCl4) or by feeding a methionine- and choline-deficient (MCD) diet. These results are associated with decreased stellate cell activation and immune cell infiltration (P<0.05). Functionally, we show that CCL3 leads to increased proliferation and migration of hepatic stellate cells in vitro. Conclusions: Our results define the chemokine CCL3 as a mediator of experimental liver fibrosis. Thus, therapeutical modulation of CCL3 might be a promising target for chronic liver diseases.