Osteoprotegerin Expression in Liver is Induced by IL13 through TGF beta

Background/Aims: Osteoprotegerin (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. Methods: Precision-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. OPG protein was measure by ELISA, whereas OPG mRNA and expression of other relevant genes was measured by qPCR. Results: In 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 alpha 1-activation and subsequent STAT6-dependent upregulation of IL13 receptor alpha 2, which in turn activates AP1 and induces production of TGF beta and subsequent production of OPG. Conclusion: We have shown that IL13 induces OPG release by liver tissue through a TGF beta-dependent pathway involving both the alpha 1 and the alpha 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.

Automated summary

This study found that IL13 induces the release of OPG in liver tissue through a TGF-beta-dependent pathway. The production of IL13 and subsequent OPG is mediated by the activation of IL13 receptors alpha 1 and alpha 2, as well as the transcription factors STAT6 and AP1.