Der Toll-like Rezeptor-TRIF Signaltransduktionsweg in der akuten Pankreatitis

急性胰腺炎（AP）是一种潜在的致死性疾病，常累及胰周组织，有时累及远处器官。疾病的严重程度取决于腺泡细胞死亡的程度和类型：虽然诱导凋亡可改善AP，但其抑制可使疾病恶化。在AP期间，从“应激”细胞释放的内源性因子（“危险”信号）的检测可能由腺泡细胞本身、邻近细胞或免疫细胞上的Toll样受体（TLR）赋予。在一组初步实验中，胰腺炎的严重程度显著恶化，并且在缺乏TLR 3和TLR 4的共同信号传导衔接蛋白（Toll/白介素-1受体结构域含有衔接蛋白TRIF）的小鼠中观察到胰腺组织坏死增加。在这个项目提案中，我们的目的是阐明这些观察到的影响是否是由于腺泡细胞中的直接TRIF功能，间接由于免疫细胞反应的调节或两者兼而有之。我们提出了一个新的概念，TRIF作为胰腺腺泡细胞凋亡和坏死之间的看门人。因此，TRIF可以控制急性胰腺炎期间的局部炎症和全身炎症反应的持续。

Acute pancreatitis (AP) is a potentially lethal disease often involving peripancreatic tissues and sometimes affecting distant organs. The severity of the disease depends on the extent and type of acinar cell death: while induction of apoptosis ameliorates AP, its inhibition worsens the disease. During AP, detection of endogenous factors (“danger” signals) released from “stressed” cells might be conferred by Toll-like receptors (TLRs) either on acinar cells themselves, on neighboring cells or on immune cells. In a preliminary set of experiments, severity of pancreatitis was strikingly worsened and increased pancreatic tissue necrosis was observed in mice lacking the common signaling adaptor protein of TLR3 and TLR4, the Toll/interleukin-1 receptor domain-containing adaptor protein, TRIF. In this project proposal, we aim at elucidating whether these observed effects are due to a direct TRIF function in acinar cells, are indirectly due to modulation of immune cell responses or both. We propose as a new concept that TRIF functions as a gatekeeper between apoptosis and necrosis in pancreatic acinar cells. Thus, TRIF may control local inflammation during acute pancreatitis and perpetuation of a systemic inflammatory response.