Backgrounds: Osteoprotegerin (OPG) is a profibrotic mediator produced by myofibroblasts under influence of transforming growth factor β (TGFβ). 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 TGFβ, interleukin (IL) 13 (IL13), IL1β, and platelet-derived growth factor BB (PDGF-BB) on expression of OPG. Results: In addition to TGFβ, only IL13 and not PDGF-BB or IL1β 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 TGFβ 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 α1-activation and subsequent STAT6-dependent upregulation of IL13 receptor α2, which in turn activates AP1 and induces production of TGFβ and subsequent production of OPG. Conclusion: We have shown that IL13 induces OPG release by liver tissue through a TGFβ-dependent pathway involving both the α1 and the α2 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 TGFβ1.

中文翻译：

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IL-13通过TGF-β诱导肝脏中的骨保护素表达

背景：骨保护素（OPG）是肌纤维母细胞在转化生长因子β（TGFβ）的影响下产生的纤维化介质。它在肝纤维化实验模型中的表达与疾病的严重程度和治疗反应密切相关。肝脏组织中OPG的调节在很大程度上是未知的，因此我们着手阐明与纤维化相关的哪些生长因子/白介素诱导OPG以及通过哪些途径。方法：使用野生动物和STAT6缺陷型小鼠的精密切割肝脏切片以及3T3成纤维细胞来研究TGFβ，白介素（IL）13（IL13），IL1β和血小板源性生长因子BB（PDGF-BB）的作用。表达OPG。结果：除了TGFβ，只有IL13而非PDGF-BB或IL1β可以诱导3T3成纤维细胞和肝切片中OPG的表达。IL13依赖性诱导在STAT6缺陷小鼠的肝脏切片中未显示，当野生型切片与TGFβ受体1激酶抑制剂galunisertib，STAT6抑制剂AS1517499或AP1抑制剂T5224共同处理时，则未显示。这表明IL13的OPG诱导作用是通过IL13受体α1的活化和随后IL13受体α2的STAT6依赖性上调介导的，IL13受体α2的激活又激活AP1并诱导TGFβ的产生和OPG的产生。结论：我们已经表明，IL13通过TGFβ依赖性途径诱导肝组织OPG释放，该途径涉及IL13的α1和α2受体以及转录因子STAT6和AP1。因此，OPG可能是治疗肝纤维化的新靶标，因为它与肝脏中纤维化的两个重要调节因子，即IL13和TGFβ1机理相关。