白介素37促进血管生成的分子机制

Interleukin-37 (IL-37) is an anti-inflammatory cytokine of the IL-1 family. IL-37 is upregualted in many angiogenesis related diseases. Notably,IL-37 shares the receptor IL-18Rα with IL-18, an angiogenic cytokine of the IL-1family. However, the regulatory mechanisms by which IL-37 regulates angiogenesis still remains unknown. In our previous work, we have found that IL-37 promoted angiogenesis in myocardial infarction model and Matrigel plug assay in vivo. IL-37 exhibited more potent angiogenic activity compared with VEGF at very low concentration in endothelial cell proliferation. IL-37 also promoted migration and tube formation in endothelial cells, and blockade of IL-18Rα inhibited the angiogenic effect of IL-37. Based on previous work, this project aim to investigate the molecular mechanisms by which IL-37 promotes angiogenesis using in vitro model of tube formation, ex vivo model of aortic ring assay and in vivo models such as myocardial infarction,Matrigel plug and oxygen induced retinopathy. We aim to determine: whether IL-18Rα mediates the angiogenic role of IL-37 both in vitro and in vivo; whether Src signaling cascade downstream of IL-18Rα mediates the angiogenic effect of IL-37; whether IL-37 regulates Src-mediated cellextracellular matrix interaction. The result will provide important theoretical basis for prevention and therapeutics of angiogenesis related diseases.

白介素37(IL-37)是IL-1 家族成员之一，具有抗炎作用。IL-37 在多种血管增生相关疾病中上调，且可与具有促血管生成功能的IL-18 受体IL-18Rα结合。然而IL-37是否调控血管生成至今未有研究涉及。我们在前期工作中发现，IL-37 在小鼠心肌缺血和基质胶模型中显著促进血管生成，在体外同等浓度下可比VEGF 有更显著促进血管内皮细胞增殖，并可促进细胞迁移及管腔形成。抗体阻断IL-18Rα可抑制IL-37 促管腔形成作用。本项目拟利用管腔形成、离体动脉环血管生成、体内心肌缺血、缺氧诱导视网膜血管生成等模型，深入研究IL-37 促进血管生成的分子机制：明确IL-18Rα是否介导IL-37促进血管生成的作用并深入探讨IL-37 通过IL-18Rα下游信号通路Src 调控血管生成的分子机制。本项目的完成将加深对IL-37 调控血管生成机制的理解，为血管生成相关疾病的治疗提供依据。

血管生成受重要生长因子和细胞因子的调控。IL-1家族成员在炎症和血管生成过程中发挥重要作用。白介素37是新发现的IL-1家族成员，其在血管生成中的调控作用仍不清楚。本项工作主要研究白介素37对血管生成的调控作用。我们发现，缺氧条件可诱导白介素37在血管内皮细胞中表达和分泌。白介素37促进血管内皮细胞增殖、管腔形成迁移和离体动脉环血管生成。白介素37可激活Erk1/2和Akt信号通路。白介素37促进体内基质胶栓血管生成、新生小鼠视网膜血管生成及缺氧诱导的视网膜血管生成。进一步研究发现，白介素37在糖尿病诱导的视网膜血管增生患者的玻璃体液内显著上升并与VEGF的浓度呈正相关，揭示了白介素37与临床疾病糖尿病增殖性视网膜病变的相关性。我们的研究发现白介素37是新型促进生理及病理血管生成的重要因子。