Role of monocyte chemoattractant protein-1 in liver fibrosis with transient myeloproliferative disorder in down syndrome.

Abstract

Liver fibrosis is a common complication associated with transient myeloproliferative disorder (TMD) in Down syndrome (DS). The exact molecular pathogenesis that regulates disease progression is largely unknown. We recently found serum and/or urinary monocyte chemoattractant protein‐1 (MCP‐1) as a novel biomarker of liver fibrosis. This study was an in vitro analysis to investigate the fibrogenic activity of MCP‐1 using the collagen‐producing LX‐2 human hepatic stellate cell line. We also examined the fibrogenic activity of serum from a male neonate with DS in whom late‐onset liver fibrosis developed even after the resolution of TMD. MCP‐1 stimulated both cell growth and collagen synthesis of LX‐2 in a dose‐dependent manner. Patient serum obtained during the active disease phase significantly up‐regulated fibrogenic activity, which was suppressed in the presence of MCP‐1‐blocking antibody. Transient transforming growth factor beta 1 stimulation primed LX‐2 to induce prolonged hypersecretion of MCP‐1 in the culture supernatant and in collagen synthesis, which was suppressed with MCP‐1 blocking antibody as well. Conclusion: MCP‐1 accounts for the prolonged activation of collagen‐producing hepatic stellate cells in both a paracrine and autocrine manner, thereby promoting liver fibrosis. Anti‐cytokine therapy targeting the fibrogenic cytokines of MCP‐1, for example, herbal medicine, could provide a new therapeutic intervention for liver fibrosis associated with TMD in DS. (Hepatology Communications 2018;2:230‐236)