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

Interleukin-1 同源物 IL-37 对肝脏炎症和纤维化的调节

• 批准号: 288401774
• 负责人: Professor Dr. Philip Clemens Reinhard Bufler
• 金额: --
• 依托单位: Klinik für Pädiatrie mit Schwerpunkt Gastroenterologie, Nephrologie und Stoffwechselmedizin (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/288401774?language=en
• 关键词: Modulation; liver; inflammation; fibrosis; Interleukin

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.

持续性炎症是慢性肝损伤的共同特征，并诱导肝纤维化、肝硬化和潜在肝癌的发展。肝枯否细胞是通过分泌免疫活性蛋白如TGF β来调节肝星状细胞功能的关键调节剂。TGF β是一种具有抗炎特性的细胞因子，并通过激活Sma和Mad相关蛋白3（Smad 3）促进肝纤维化。我们报道了一种新的白细胞介素-1家族细胞因子IL-37与Smad 3相互作用。在细胞刺激后，IL 37易位到细胞核，可能与Smad 3一起调节转录活性。当内源性Smad 3耗尽时，IL-37转基因小鼠对脂多糖的炎症反应增加，表明两种蛋白质的功能合作。IL-37也分泌在刺激的细胞的上清液中。细胞外IL-37通过结合IL 18 Ra和募集抗炎性单受体Ig样受体SIGIRR而具有活性。总之，IL-37似乎是IL-1家族的独特细胞因子，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，从IL-37 tg小鼠中分离的肝枯否细胞与野生型枯否细胞相比，对LPS的炎症反应显著降低。其他研究表明，重组IL-37可抑制小鼠枯否细胞活性和缺血诱导的肝损伤。我们认为IL-37通过下调IL-1b和与TGF β依赖性通路的相互作用来调节肝脏炎症和随后的纤维化。这项研究提案的结果将显示靶向IL-37是否可能是炎症和纤维化肝脏疾病的有用治疗策略。

项目成果

Beneficial effects of IL-37 after spinal cord injury in mice

• DOI: 10.1073/pnas.1523212113
• 发表时间: 2016-02-02
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Coll-Miro, Marina;Francos-Quijorna, Isaac;Lopez-Vales, Ruben
• 通讯作者: Lopez-Vales, Ruben

Role for nuclear interleukin-37 in the suppression of innate immunity

• DOI: 10.1073/pnas.1821111116
• 发表时间: 2019-03-05
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Li, Suzhao;Amo-Aparicio, Jesus;Dinarello, Charles A.
• 通讯作者: Dinarello, Charles A.

Interleukin-37 Inhibits Colon Carcinogensis During Chronic Colitis

• DOI: 10.3389/fimmu.2019.02632
• 发表时间: 2019-11
• 期刊: Frontiers in Immunology
• 影响因子: 7.3
• 作者: S. Mountford;A. Ringleb;R. Schwaiger;D. Mayr;S. Kobold;C. Dinarello;P. Bufler