Fas信号诱导树突状细胞分泌IL-1β的分子机制及其在自身免疫性疾病进展中作用的研究

Fas signaling can induce DCs to secret IL-1β but the mechanism remains largely unknown. We found that engagement of Fas receptor on DCs increased its tyrosine phosphorylation, activated PLC-γ2, triggered calcium release of endoplasmic reticulum and activated ERK. Activated ERK bound and activated membrane channel protein Pannexin 1, which increased extracellular release of ATP. Then, ATP activated inflammasome, leading to IL-1β release. DCs can induce T cell activation followed by upregulation of FasL. In addition, we found that in the course of DC-T cell interaction, CD4+ T cells promoted Th17 cell differentiation via Fas and IL-1 of DCs. Given the central role of Th17 cells in the progression of autoimmune disease, we hypothesize: ①Fas receptor may activate PLC-γ2 through binding some tyrosine kinase by its phosphorylated tyrosine residue; ②ERK may regulate activity of Pannexin 1 by phosphorylated its serine/threonine residues; ③Enhahced Th17 cell differentiation induced by IL-1β from DCs after ligation of Fas receptor by DC-activated CD4+ T cells may promote autoimmune disease development. In this project, we will further testify these hypotheses.

Fas信号能诱导DCs分泌IL-1β，但相关机制仍不清楚。我们发现，交联DCs的Fas受体可增加Fas受体酪氨酸残基的磷酸化，活化PLC-γ2，引起内质网钙释放，活化ERK。ERK能结合并活化膜通道蛋白Pannexin 1，促进ATP释放及炎症小体活化，导致IL-1β释放。DCs可诱导T细胞活化及其FasL的表达。此外，我们发现，DC-T细胞作用过程中，CD4 T可依赖Fas诱导DC分泌IL-1，介导自身往Th17细胞分化。而Th17细胞可加速自身免疫性疾病的进展。因此，我们推测：①Fas受体可通过磷酸化的酪氨酸残基结合某酪氨酸激酶来活化PLC-γ2；②ERK可磷酸化Pannexin 1的丝氨酸/苏氨酸位点来调节Pannexin 1的活性；③DCs活化的CD4 T细胞交联DCs的Fas信号后，DCs分泌的IL-1β可促进Th17细胞分化而加速自身免疫病的进展。本课题我们拟深入验证以上假说。

Fas信号诱导树突状细胞（DCs）分泌IL-1β，但相关机制仍不清楚。我们发现，交联DCs的Fas受体可增加Fas受体胞内段第283位酪氨酸残基磷酸化，随后招募Syk激酶并活化PLC-γ2，引起内质网钙释放，活化ERK。ERK能结合并活化膜通道蛋白Pannexin 1的第205位丝氨酸活性，促进ATP释放及炎症小体活化，导致IL-1β释放。此外，我们发现，DC-T细胞作用过程中，CD4+T细胞诱导DC分泌的IL-1β促进自身往Th17细胞分化，而Th17细胞可加速肠炎等自身免疫性疾病的进展。我们的研究成果将揭示在DC-T细胞相互作用的过程中，T细胞通过Fas-FasL对DCs的反馈作用及其病理作用；调控Pannexin 1通道蛋白活性的新机制及Fas受体介导的新信号通路，从而为肠炎等自身免疫性疾病的治疗提供新思路。