Renal tubular epithelial-myofibroblast transdifferentiation (EMT) plays a central role in the development of renal interstitial fibrosis (RIF). The profibrotic cytokine interleukin (IL)-1 and the IL-1 receptor (IL-1R) also participate in RIF development, and Toll/IL-1R 8 (TIR8), a member of the Toll-like receptor superfamily, has been identified as a negative regulator of IL-1R signaling. However, the functions of TIR8 in IL-1-induced RIF remain unknown. Here, human embryonic kidney epithelial cells (HKC) and unilateral ureteric obstruction (UUO)-induced RIF models on SD rats were used to investigate the functions of TIR8 involving IL-1β-induced EMT. We showed that IL-1β primarily triggers TIR8 expression by activating nuclear factor-κB (NF-κB) in HKC cells. Conversely, high levels of TIR8 in HKC cells repress IL-1β-induced NF-κB activation and inhibit IL-1β-induced EMT. Moreover, in vitro and in vivo findings revealed that TIR8 downregulation facilitated IL-1β-induced NF-κB activation and contributed to TGF-β1-mediated EMT in renal tubular epithelial cells. These results suggested that TIR8 exerts a protective role in IL-1β-mediated EMT and potentially represents a new target for RIF treatment.

肾小管上皮-肌成纤维细胞转分化（EMT）在肾间质纤维化（RIF）的发展中起着核心作用。纤维化细胞因子白介素（IL）-1和IL-1受体（IL-1R）也参与RIF的发展，并且已确定Toll / IL-1R 8（TIR8）是Toll样受体超家族的成员作为IL-1R信号的负调节剂。然而，TIR8在IL-1诱导的RIF中的功能仍然未知。在这里，人类胚胎肾上皮细胞（HKC）和单侧输尿管阻塞（UUO）诱导的SD大鼠RIF模型用于研究TIR8涉及IL-1β诱导的EMT的功能。我们显示IL-1β主要触发TIR8通过激活HKC细胞中的核因子-κB（NF-κB）表达。相反，HKC细胞中高水平的TIR8抑制IL-1β诱导的NF-κB活化并抑制IL-1β诱导的EMT。此外，体外和体内发现表明，TIR8下调促进了IL-1β诱导的NF-κB活化，并促进了肾小管上皮细胞中TGF-β1介导的EMT。这些结果表明，TIR8在IL-1β介导的EMT中发挥保护作用，并可能代表RIF治疗的新靶标。