Osteoprotegerin expression in liver is induced by IL-13 through TGF-β

1.BackgroundsOsteoprotegerin (OPG) is a profibrotic mediator produced by myofibroblasts under influence of transforming growth factor {beta} (TGF{beta}). 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 growth factors/interleukins associated with fibrosis induce OPG and through which pathways. MethodsPrecision-cut liver slices of wild type and STAT6-deficient mice and 3T3 fibroblasts were used to investigate the effects of TGF{beta}, interleukin (IL) 13 (IL13), IL1{beta}, and platelet-derived growth factor BB (PDGF-BB) on expression of OPG. ResultsIn addition to TGF{beta}, only IL13 and not PDGF-BB or IL1{beta} could induce OPG expression in 3T3 fibroblasts and liver slices. This IL13-dependent induction was not shown in liver slices of STAT6-deficient mice and when wild type slices were cotreated with TGF{beta} receptor 1 kinase inhibitor galunisertib, STAT6 inhibitor AS1517499, or AP1 inhibitor T5224. This suggests that the OPG-inducing effect of IL13 is mediated through IL13 receptor 1-activation and subsequent STAT6-dependent upregulation of IL13 receptor 2, which in turn activates AP1 and induces production of TGF{beta} and subsequent production of OPG. ConclusionWe have shown that IL13 induces OPG release by liver tissue through a TGF{beta}-dependent pathway involving both the 1 and the 2 receptor of IL13 and transcription factors STAT6 and AP1. OPG may therefore be a novel target for the treatment liver fibrosis as it is mechanistically linked to two important regulators of fibrosis in liver, namely IL13 and TGF{beta}1.