TRAF6 as the Key Adaptor of TLR4 Signaling Pathway Is Involved in Acute Pancreatitis
TRAF6 as the Key Adaptor of TLR4 Signaling Pathway Is Involved in Acute Pancreatitis
复制标题
DOI：
10.1097/mpa.0b013e3181bb9073
复制
发表时间：
2010-04
期刊：
影响因子：
2.9
通讯作者：
Xiang-Yu Zhou;Zongguang Zhou;Jun-li Ding;Ling-yan Wang;Rong Wang;Bin Zhou;Jun Gu;Xiao-Feng Sun;Yuan Li
中科院分区：
文献类型：
--
作者：
Xiang-Yu Zhou;Zongguang Zhou;Jun-li Ding;Ling-yan Wang;Rong Wang;Bin Zhou;Jun Gu;Xiao-Feng Sun;Yuan Li
目的：研究肿瘤坏死因子受体相关因子6（TRAF 6）作为Toll样受体4（TLR 4）信号通路的关键调节子在小鼠急性胰腺炎（AP）中的潜在作用。方法：采用7次腹腔注射雨蛙肽诱导TLR 4缺陷型（TLR 4-Def）和野生型（TLR 4-WT）小鼠急性胰腺炎模型。根据病理学研究对炎症严重程度进行评分和评估。TRAF 6的表达通过逆转录聚合酶链反应、蛋白质印迹和免疫组织化学测定。结果：两种小鼠均能成功诱导急性胰腺炎，但炎症进展不同。TLR 4-Def小鼠胰腺炎症反应先钝后轻，然后逐渐增强，至晚期达到高峰;而TLR 4-WT小鼠胰腺炎症反应启动快，至AP早期达到高峰，随后逐渐减轻。TLR 4-Def小鼠的TRAF 6表达显著高于TLR 4-WT小鼠。免疫组化显示TRAF 6主要表达于胰腺腺泡细胞。结论：TLR 4-TRAF 6信号通路参与AP的发生发展。TLR 4以外的其他信号通路可能通过TRAF 6参与胰腺炎症过程。TRAF 6作为TLR 4依赖性和TLR 4非依赖性信号通路的交汇点，在AP中发挥重要作用。AP -急性胰腺炎，CIP -蛙皮素诱导的胰腺炎，IL-4 -白细胞介素4，IL-6 -白细胞介素6，IL-10 -白细胞介素10，LPS -脂多糖，IRAK IL-1 -受体相关激酶，MyD 88-髓样分化因子88，NF-B -核因子-B，实时RT-PCR -实时逆转录聚合酶链反应，TAB-TAK 1-结合蛋白，TAK 1-转化生长因子-活化激酶1，TLR 4-toll样受体4，TRAF -肿瘤坏死因子受体相关因子
Objectives: To study the potential role of tumor necrosis factor receptor-associated factor 6 (TRAF6) as the key adaptor of the toll-like receptor 4 (TLR4) signaling pathway in acute pancreatitis (AP) in mice. Methods: Acute pancreatitis was induced by 7 intraperitoneal injections of cerulein in TLR4-deficient (TLR4-Def) and TLR4 wild-type (TLR4-WT) mice. Inflammatory severity was scored and evaluated based on pathological study. TRAF6 expression was determined by reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemistry. Results: Acute pancreatitis was successfully induced in both mice strains, but the inflammatory progression was different. In TLR4-Def mice, pancreatic inflammation was blunt and mild first, then became increasingly intensive and peaked at the later stage, whereas in the TLR4-WT mice, the response was fast initiated and peaked at the early stage of AP, then alleviated gradually. TRAF6 expression in TLR4-Def mice was significantly higher than that in the TLR4-WT mice. Immunohistochemistry located TRAF6 expressed mainly in the pancreatic acinar cells. Conclusions: The TLR4-TRAF6 signaling pathway is critically involved in AP. Other signaling pathways beyond TLR4 may participate in the pancreatic inflammatory process via TRAF6. As a convergence point of the TLR4-dependent and the TLR4-independent signaling pathways, TRAF6 plays an important role in AP.Abbreviations: AP - acute pancreatitis, CIP - cerulein-induced pancreatitis, IL-4 - interleukin 4, IL-6 - interleukin 6, IL-10 - interleukin 10, LPS - lipopolysaccharide, IRAK IL-1 - receptor-associated kinase, MyD88 - myeloid differentiation factor 88, NF-B - nuclear factor-B, real-time RT-PCR - real-time reverse transcriptase polymerase chain reaction, TAB - TAK1-binding proteins, TAK1 - transforming growth factor--activated kinase 1, TLR4 - toll-like receptor 4, TRAF - tumor necrosis factor receptor-associated factor