| Abstrak/Abstract |
Our previous studies have shown that osteoprotegerin (OPG) is a profibrotic mediator, produced by myofibroblasts, under influence of TGF?. Its expression in experimental models of liver fibrosis correlates well with disease severity and treatment responses. The regulation of OPG in liver tissue is largely unknown and we therefore set out to elucidate which cytokines associated with fibrosis induce OPG and through which
pathways it can induce fibrotic responses.
Methods: Precision-cut liver slices of wild type and STAT6(?/?) mice and 3T3 fibroblasts were used to investigate the effects of TGF?, IL13, IL1?, and PDGF-BB on expression of OPG and several markers of fibrosis: procollagen 1?1 (Col1?1), ?-smooth muscle actin (?-SMA), heat shock protein 47 (HSP47), plasminogen activator inhibitor 1 (PAI1), and fibronectin 2 (Fn2).
Results: In addition to TGF?, only IL13 and not PDGF-BB or IL1? could induce OPG expression in 3T3 fibroblasts and liver slices. This induction was not shown in liver slices of STAT6(?/?) mice and when wild type slices were cotreated with TGF? receptor 1 kinase inhibitor Galunisertib, suggesting that the OPG-inducing effect of IL13 is mediated through STAT6-dependent TGF? production, which in turn can induce OPG. In more detail, this IL13-induced TGF? production is mediated through IL13 receptor ?1-activation and subsequent STAT6-dependent upregulation of IL13 receptor ?2. The IL13 was then found to signal through the ?2 receptor to induce expression of TGF?. Furthermore, treatment of liver slices with OPG resulted in higher
expression of fibrosis markers especially Col-1?1 and TGF?, which could be inhibited by co-treatment with Galunisertib, indicating the importance of TGF? in this pathway.
Conclusions: IL13 indirectly induces OPG production through STAT6-dependent regulation of IL13 receptor ?2, which then leads to increased expression of TGF? followed by upregulation of OPG production. The profibrotic activity of OPG is also dependent on TGF?. Both results show that OPG and TGF? are involved in a feed-forward loop during development of liver fibrosis. |
