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

持续性炎症是慢性肝损伤的共同特征，可导致肝纤维化、肝硬变和潜在的肝癌。肝枯否细胞是肝星状细胞功能的关键调节者，通过分泌免疫活性蛋白如转化生长因子β。转化生长因子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)促进肝纤维化。我们报道了白介素1家族的一种新的细胞因子IL-37与SMAD3相互作用。在细胞刺激后，IL 37移位到细胞核，可能与Smad3共同调节转录活动。当内源性Smad3被耗尽时，IL-37转基因小鼠对内毒素的炎症反应增强，表明两种蛋白功能协同。IL-37也在刺激细胞的培养上清液中分泌。细胞外IL-37通过与IL18Ra结合和募集抗炎性单一受体Ig样受体SIGIRR而激活。综上所述，IL-37似乎是IL-1家族中的一种独特的细胞因子，因为它能够干扰转化生长因子β的信号级联，从而调节炎症。IL-37表达于人肝细胞和胆管上皮细胞。我们证明，与野生型Kupffer细胞相比，从IL-37tg小鼠分离的肝脏Kupffer细胞对内毒素的炎症反应显著降低。另有研究表明，重组IL-37可抑制库普弗细胞活性和小鼠缺血诱导的肝损伤。我们认为，IL-37通过下调IL-1b-β和与TGFβ依赖的途径相互作用来调节肝脏炎症和随后的纤维化形成。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.