Interestingly, factor(s) produced in supernatants in response to HCV from slow progressors, in whom TGFβ blockade increased IHL effector IFNγ response, had an antifibrotic effect on human HSC, and treating these supernatants with anti-TGFβ antibodies abrogated fibrolytic gene expression by HSC. Conversely, no such effect was observed with rapid progressors for whom TGFβ blockade had no such enhancing effect. Such apparently paradoxical observations for TGFβ, most often considered a profibrogenic cytokine, could be explained because TGFβ is a multifunctional cytokine that modulates its function depending on the cell type producing it
and other factors present with it or induced by it. In this regard, regulatory IL-10 might also be involved. In a fibrosis mouse
model, for example, TGFβ gene therapy lead to the appearance of cells producing IL-10.32 selleck TGFβ “gene therapy” ameliorated fibrosis in wildtype, but not IL-10-deficient mice, and induced Smad4, which then binds to and activates the IL-10 promoter. In our study, we observed a significant production of IL-10 by IHL in response to HCV and peripheral HCV-specific IL-10 data did not exclude its participation in suppressive activity. Although too preliminary Hydroxychloroquine to formally conclude, it is possible that when TGFβ is locally produced by HCV-specific Treg it induces substantial amounts of other cytokines, including IL-10, that
participate to counterbalance the profibrogenic MCE effect of TGFβ produced by other surrounding hepatic cells. Whether IL-10 and/or other factors contribute to explain the antifibrotic effect of Treg TGFβ will be the object of our future studies. In conclusion, these results suggest that TGFβ produced locally by Tregs suppresses, rather than enhances, hepatic fibrogenesis. The data also suggest that suppression is in part in concert with other regulatory factor(s) secreted by intrahepatic lymphocytes in response to HCV. Tregs have been associated with HCV persistence in chronic HCV infection.13, 14, 36 However, they may play a more beneficial antiinflammatory role by locally protecting against surrounding tissue damage. Failure to develop appropriate effector and regulatory HCV-specific T-cell responses presumably serves to drive HCV-related liver fibrosis. A better understanding of the opposing effects and roles of different T cell subsets could provide novel tools allowing maintenance of such a beneficial balance, suggesting novel therapeutic approaches to prevent HCV-mediated liver disease progression. Data acquisition, analysis: S.L., L.V., I.A.N., Y.P. Providing samples, clinical consulting: N.H.A., D.S., M.J.K. Funding/material support: M.J.K., M.A.E., N.A. Data interpretation, revision: N.A., D.S., M.A.E. Study concept, design, draft: N.A.