Sequential Matrix Metalloproteinase-1 Expression Triggered by Infiltrating Monocytic Lineage Cells Modulates Pathophysiological Aspects of Human Nonalcoholic Steatohepatitis

摘要

Background/Aims: Matrix metalloproteinase-1 (MMP-1) is a key enzyme in collagen metabolism and tissue remodeling. We previously reported that MMP-1 expression in monocytes and other types of cells in the liver is associated with disease progression in patients with nonalcoholic steatohepatitis (NASH). To further implicate MMP-1 up-regulation in NASH pathogenesis, we examined dynamic and sequential MMP-1 expression in peripheral blood monocytes and cells in steatotic liver, and attempted to elucidate the mechanism of MMP-1 induction. Methods: Twenty-nine NASH patients and 26 non-NASH subjects were recruited in the study. Their peripheral blood mononuclear cells were isolated and analyzed by fluorescence-activated cell sorting, and liver specimens were subjected to confocal laser-scanning and immunoelectron microscopic examinations. Peripheral blood monocytic lineage cells were co-cultured with steatotic hepatocytes obtained from biopsy specimens to examine MMP-1 induction. Results: Infiltrating monocytes were the earliest to acquire an MMP-1-expressing phenotype among all investigated cell types in early-stage NASH liver. On the other hand, circulating monocytes did not express significant levels of MMP-1 mRNA or protein before infiltrating steatotic liver. Co-culture with steatotic hepatocytes induced MMP-1 expression in otherwise MMP-1-negative peripheral blood monocytic lineage cells. As disease progressed, MMP-1 was sequentially expressed by other types of cells in NASH liver. Notably, clusters of OV-6- or CK19-positive hepatic progenitor cells with a morphological feature of ductular reaction showed strong MMP-1 staining in advanced-stage NASH. Conclusion: MMP-1 up-regulation in infiltrating monocytic lineage cells represents an initial event in early-stage NASH and, together with the subsequent expression in other types of cells, modulates pathophysiological aspects of NASH.