Nishida Atsushi, Inatomi Osamu, Fujimoto Takehide, Imaeda Hirotsugu, Tani Masaji, Andoh Akira
From the Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
Pancreas. 2017 Apr;46(4):539-548. doi: 10.1097/MPA.0000000000000765.
Interleukin-36 (IL-36) is a recently described proinflammatory cytokine, characterized by the induction of inflammatory mediators. In the present study, we investigated the biological activity and the signal transduction of IL-36α in human pancreatic myofibroblasts.
The mRNA and protein expression of inflammatory mediators was evaluated using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of IL-36α and its receptor in the pancreatic tissue was evaluated using immunohistochemical technique. Intracellular signaling pathways were evaluated using immunoblotting and specific small interference RNA-transfected cells.
Interleukin-36α and its receptor complex IL-36R/IL-1RAcP were detected in fibrotic tissue of chronic pancreatitis. Interleukin-36α dose- and time-dependently induced the mRNA expression and protein secretion of CXCL1, CXCL8, MMP-1, and MMP-3 from human pancreatic myofibroblasts. Interleukin-36α assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex. Furthermore, IL-36α induced the phosphorylation of mitogen-activated protein kinases and the activation of nuclear factor κB and activator protein 1. Mitogen-activated protein kinase inhibitors and small interference RNAs specific for nuclear factor κB and activator protein 1 significantly suppressed the protein secretion of inflammatory mediators induced by IL-36α stimulation.
It was suggested that IL-36α plays an important role in the pathophysiology of inflammation and fibrosis in the pancreas via an autocrine function.
白细胞介素-36（IL-36）是一种最近被描述的促炎细胞因子，其特征在于可诱导炎症介质。在本研究中，我们调查了IL-36α在人胰腺肌成纤维细胞中的生物学活性和信号转导。
分别使用实时聚合酶链反应和酶联免疫吸附测定法评估炎症介质的mRNA和蛋白质表达。使用免疫组织化学技术评估胰腺组织中IL-36α及其受体的表达。使用免疫印迹和特异性小干扰RNA转染的细胞评估细胞内信号通路。
在慢性胰腺炎的纤维化组织中检测到白细胞介素-36α及其受体复合物IL-36R/IL-1RAcP。白细胞介素-36α剂量和时间依赖性地诱导人胰腺肌成纤维细胞中CXCL1、CXCL8、MMP-1和MMP-3的mRNA表达和蛋白质分泌。白细胞介素-36α将髓样分化因子88（MyD88）衔接蛋白（MyD88、TRAF6、IRAK1和TAK1）组装成复合物。此外，IL-36α诱导丝裂原活化蛋白激酶的磷酸化以及核因子κB和活化蛋白1的激活。丝裂原活化蛋白激酶抑制剂以及针对核因子κB和活化蛋白1的小干扰RNA显著抑制了IL-36α刺激诱导的炎症介质的蛋白质分泌。
提示IL-36α通过自分泌功能在胰腺炎症和纤维化的病理生理学中起重要作用。
