IL-18与IL-3协同调控胰腺星状细胞STAT3/IL-4通路在慢性胰腺炎中的作用机制研究

慢性胰腺炎（CP）发病机制不明，致使缺乏针对性治疗而严重危及人类健康。近期研究发现细胞焦亡相关因子IL-18在多种纤维化疾病中发挥关键作用，然而，其在CP中的作用尚未见报道。我们构建转基因小鼠CP模型发现：CP胰腺组织中IL-18受体IL-18Rα高表达且主要定位于胰腺星状细胞（PSCs），IL-18Rα敲除明显减轻CP。体外研究还发现：PSCs中IL-18Rα上调不受IL-18调控，而受IL-3调控，IL-3存在时IL-18仍不能活化PSCs，但可磷酸化STAT3而促进IL-4分泌，IL-4再诱导巨噬细胞M2型极化，据此，我们提出IL-18在IL-3协同下通过调控PSCs内STAT3/IL-4通路以诱导巨噬细胞M2型极化而加重CP的科学假设。本项目拟通过收集临床标本、构建转基因小鼠CP模型及提取原代细胞并进行相关干预以探究IL-18在CP中的作用及其机制，为临床治疗CP提供新靶点。

chronic pancreatitis (CP) seriously endangers the health of human due to the lack of etiological therapy under its ambiguous mechanism. Recently, it has been shown that IL-18 that is a pyroptosis associated cytokine plays the key role in various fibrotic deseases. However, the role of IL-18 in CP remains unclear. Our preliminary studies by establishing CP model of wild-type and transgenic mice showed that IL-18 receptor α (IL-18Rα) was significantly upregulated and mainly located in the pancreatic stelate cells, and importantly deletion of IL-18Rα obviously alleviated the severity of CP. Furthermore, we found by in-vitro experiments that the up-regulation of IL-18Rα in PSCs was induced by IL-3 but not IL-18. Moreover, IL-18 didn’t exert the property of activating PSCs but phosphorylated STAT3 to induce PSCs to produce IL-4 in present of IL-3, and produced IL-4 further promoted macrophage M2 polarization. Given all this, we postulate that IL-18 induces pancreatic fibrosis by indirectly inducing macrophage M2 polarization via promoting STAT3/IL-4 pathway of PSCs in present of IL-3 . We will further collect sample of CP patients and establish CP model of IL-18R1-/-mice and isolate primary cells which will be treated accordingly to expound the role of IL-18 in CP and its mechanism to afford a new therapeutic target for CP.