Alcohol affects the cross-talk between hepatocytes and hepatic stellate cells in HCV infection

The course of HCV infection is exacerbated by alcohol exposure, and the progression of this viral disease depends on fibrosis development. However, the exact mechanisms of how alcohol- exposed HCV infected hepatocytes affect... [ view full abstract ]

The course of HCV infection is exacerbated by alcohol exposure, and the progression of this viral disease depends on fibrosis development. However, the exact mechanisms of how alcohol- exposed HCV infected hepatocytes affect the hepatic stellate cells (HSC), a key player in the development of fibrosis, is unknown. Previously, we have shown that the major ethanol metabolite, acetaldehyde (Ach) induces apoptosis in HCV-sensitized hepatocytes. The goal of this study was to investigate whether apoptotic hepatocytes induce activation of HSC to promote the progression to fibrosis. UV light-exposed control and HCV-infected Huh7.5 cells treated or not with Ach continuously produced by enzymatic acetaldehyde-generating system (AGS) were used as a source of apoptotic bodies (AB). Then, HSC cell line LX2 was exposed to the generated AB at a 1:3 ratio. After 2-8 h of incubation, mRNAs of cytokines, chemokines and prostaglandin D and E receptors were measured by RT-PCR. We found that IL-8, MCP1 and MIP2 expression were higher in HSC incubated with AB from HCV⁺ Huh7.5 cells (AB _HCV); these levels were further increased if AB from AGS-treated cells (AB_AGS) were used. Importantly, AB_HCV enhanced collagen 1 (Col1A1), while TGFβ expression was stimulated by AB_AGS. We also observed induction of PGD-R2 mRNA in HSC exposed to AB_AGS, and this effect was more prominent with AB from HCV-infected cells, indicating that both HCV and Ach contribute to the switch of HSC from inflammatory to a pro-fibrotic phenotype. Thus, we conclude that the HSC-hepatocytes contact via apoptotic bodies that contain HCV and Ach-modified proteins may drive the progression of fibrosis in HCV-infected alcohol consumers.