In vitro, S100-MPs are released from human T cells after activation (and apoptosis) and fuse with the cell membranes of HSCs and transfer membrane molecules (CD147, Emmprin), which triggers up-regulation of fibrolytic MMP-1, MMP-3, MMP-9, and MMP-13. Of note,
the circulating CD4+ and CD8+ S100-MPs found in patients’ plasma mainly derive from activated T cells, and their equivalent generated ex vivo by PHA stimulation of donor CD4+ and CD8+ T cells most strongly up-regulated putatively fibrolytic MMPs in HSCs (Table 1). This finding will likely have relevance in vivo, because activated HSCs are the principal driving force of liver Proteasome inhibitor drugs fibrogenesis. MPs were described as a product of various kinds of cell types, including T cells, as a product of activation or early apoptosis. However, characterization of the biological effects of these MPs has been limited. A prior study implicated MPs from the Jurkat T cell line in fibrolytic activation of synovial fibroblasts.8 Questions relevant to liver disease or diseases of other epithelial-mesenchymal organs have not been addressed. We demonstrated that increased T cell activation (and apoptosis) in active hepatitis C19 is paralleled by
excess release of T cell–derived buy Vadimezan MPs, which can be detected in the circulation. Using T cell subpopulations and HSCs, both of which are key players in liver inflammation and fibrogenesis, we demonstrated the functional relevance of these MPs in vitro. Therefore, T cell MPs ameliorated or even blunted the fibrogenic response that is usually prevalent in chronic hepatitis,1 including the neutralization of fibrogenic activation of HSCs by TGFβ1, the strongest profibrogenic cytokine in hepatic fibrosis and other fibrotic diseases.2 Of note, not all T cell–derived MPs were equally potent inducers of fibrolytic MMP expression selleck chemicals llc in HSCs. Therefore, MPs derived from apoptotic and activated CD8+ T cells were the strongest inducers compared with MPs from activated CD4+
T cells or from the CD4-expressing Jurkat T cell line (Table 1). In this regard, it is noteworthy that CD8+ cells predominate in livers with hepatitis C, and the presence of CD8+ rather than CD4+ T cells has been correlated with the progression of liver fibrosis.20-22 These contrast with circulating MPs in inflammatory intestinal diseases where CD4+ T cell–derived MPs predominate (unpublished data). Therefore, MPs derived from activated (and apoptotic) CD8+ and CD4+ T cells may represent a negative feedback loop that counteracts the yet ill-defined profibrogenic activity of T cells once they become highly stimulated (as reproduced in vitro with PHA) with or without subsequent deletion by apoptosis. Human T cell–derived MPs could also potently induce MMP expression in primary HSCs from rats, suggesting a conserved mechanism, which is working beyond species boundaries.