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 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 ma... More
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 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. 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. ( 2018;2:230-236).
