Modulation of liver inflammation and fibrosis by the Interleukin-1 homologue IL-37

持续的炎症是慢性肝损伤的共同特征，可诱发肝纤维化、肝硬化和潜在的肝癌。肝库普弗细胞是肝星状细胞功能的关键调节剂，通过分泌免疫活性蛋白，如tgf - β。tgf β是一种具有抗炎特性的细胞因子，通过激活Sma-和mad相关蛋白3 （Smad3）来促进肝纤维化。我们报道了IL-37，一种新的白细胞介素-1家族的细胞因子，与Smad3相互作用。细胞刺激后，IL - 37转运到细胞核，可能与Smad3协同调节转录活性。当内源性Smad3缺失时，il -37转基因小鼠对脂多糖的炎症反应增加，表明两种蛋白的功能合作。受刺激细胞的上清液中也分泌IL-37。细胞外IL-37通过结合IL18Ra和募集抗炎单受体igg样受体SIGIRR而具有活性。总之，IL-37似乎是IL-1家族中独特的细胞因子，通过其干扰tgf - β信号级联的能力来调节炎症。IL-37在人肝细胞和胆管上皮中表达。我们证明，与野生型库普弗细胞相比，IL-37tg小鼠分离的肝库普弗细胞对LPS的炎症反应明显降低。其他研究表明，重组IL-37抑制小鼠库普弗细胞活性和缺血引起的肝损伤。我们提出IL-37通过下调IL-1b和与tgfβ依赖通路的相互作用来调节肝脏炎症和随后的纤维化。这项研究计划的结果将表明靶向IL-37是否可能成为炎症性和纤维化性肝病的有效治疗策略。

Sustained inflammation is a common characteristic of chronic liver injury and induces the development of liver fibrosis, cirrhosis and potentially liver cancer. Liver Kupffer cells are key modulators of hepatic stellate cell function by secretion of immunologically active proteins such as TGFbeta. TGFbeta is a cytokine with anti-inflammatory properties and promotes liver fibrosis via the activation of Sma- and Mad-related protein 3 (Smad3). We reported that IL-37, a novel cytokine of the interleukin-1 family, interacts with Smad3. After cell stimulation IL 37 translocates to the nucleus, possibly in concert with Smad3 to regulate transcriptional activity. The inflammatory response to lipopolysaccharide in IL-37-transgenic mice was increased when endogenous Smad3 was depleted indicating a functional cooperation of both proteins. IL-37 is also secreted in the supernatant of stimulated cells. Extracellular IL-37 is active by binding to the IL18Ra and recruitment of anti-inflammatory single receptor Ig-like receptor SIGIRR. In summary, IL-37 appears to be a unique cytokine of the IL-1 family through its ability to interfere with the signaling cascade of TGFbeta in order to modulate inflammation. IL-37 is expressed in human hepatocyte and bile duct epithelia. We demonstrated that isolated hepatic Kupffer cells from IL-37tg mice have a markedly reduced inflammatory response to LPS in comparison to wild-type Kupffer cells. Others showed that recombinant IL-37 inhibits Kupffer cell activity and ischemia-induced liver damage in mice. We propose that IL-37 modulates liver inflammation and subsequent fibrogenesis by downregulation of IL-1b- and interaction with TGFbeta-dependent pathways. The results of this research proposal will show whether targeting IL-37 could be a useful therapeutic strategy in inflammatory and fibrogenic liver diseases.