Department of Medicine, Shiga University of Medical Science, Seta-Tukinowa, Otsu 520-2192, Japan.
Gut. 2010 Apr;59(4):531-41. doi: 10.1136/gut.2009.193599. Epub 2009 Dec 8.
Interleukin 33 (IL33) is a cytokine belonging to the IL1 family and it binds to a complex of the ST2L/IL1 receptor accessory protein (IL1RAcP). To define the role of IL33 in fibrogenesis of the pancreas, the expression of IL33, ST2L and IL1RAcP was examined in chronic pancreatitis tissues. The effects of IL33 on the functions of human pancreatic myofibroblasts were also investigated.
Tissue samples were obtained surgically. The expression of IL33, ST2L and IL1RAcP was evaluated by standard immunohistochemical procedures. Messenger RNA expression for IL33, ST2L and IL1RAcP was analysed by northern blotting and real-time PCR analyses, and protein expression was assessed by western blotting and ELISA. Cell proliferation and migration were assessed by a (3)H-thymidine incorporation assay and the modified Boyden chamber assay, respectively.
IL33, ST2L and IL1RAcP were expressed by alpha-SMA-positive myofibroblasts in the fibrosis of chronic pancreatitis. In human pancreatic myofibroblasts, IL33 was weakly immunoexpressed without any stimuli, and this was markedly enhanced by IL1beta, tumour necrosis factor alpha (TNFalpha) and lipopolysaccharide (LPS) via the mitogen-activated protein kinase (MAPK)-dependent AP-1 activation pathway. ST2L mRNA was weakly detected in unstimulated cells, and IL4 and interferon gamma (IFNgamma) strongly enhanced ST2L expression via STAT6 and STAT1 signalling, respectively. IL33 rapidly induced the phosphorylation of MAPKs and IkappaBalpha, and enhanced the expression of inflammatory mediators (IL6, IL8, IP-10, Gro-alpha, Gro-beta and MCP-1) in IL4- or IFNgamma-pretreated cells. IL33 stimulated the proliferation and migration of pancreatic myofibroblasts.
IL33 and its receptor complex (ST2L and IL1RAcP) constitute a novel signalling system which may play an important role in the pathogenesis of chronic pancreatitis.
白细胞介素 33（IL33）是一种细胞因子，属于白细胞介素 1 家族，它与 ST2L/白细胞介素 1 受体辅助蛋白（IL1RAcP）复合物结合。为了确定 IL33 在胰腺纤维化中的作用，研究了慢性胰腺炎组织中 IL33、ST2L 和 IL1RAcP 的表达。还研究了 IL33 对人胰腺成肌纤维细胞功能的影响。
通过手术获得组织样本。通过标准免疫组织化学程序评估 IL33、ST2L 和 IL1RAcP 的表达。通过 northern blot 和实时 PCR 分析分析 IL33、ST2L 和 IL1RAcP 的信使 RNA 表达，通过 western blot 和 ELISA 评估蛋白表达。通过（3）H-胸腺嘧啶掺入测定和改良 Boyden 室测定分别评估细胞增殖和迁移。
IL33、ST2L 和 IL1RAcP 由慢性胰腺炎纤维化中的 alpha-SMA 阳性成肌纤维细胞表达。在人胰腺成肌纤维细胞中，IL33 在没有任何刺激的情况下弱免疫表达，并且通过丝裂原活化蛋白激酶（MAPK）依赖性 AP-1 激活途径被 IL1beta、肿瘤坏死因子 alpha（TNFalpha）和脂多糖（LPS）显著增强。未刺激的细胞中检测到弱的 ST2L mRNA，IL4 和干扰素 gamma（IFNgamma）分别通过 STAT6 和 STAT1 信号转导强烈增强 ST2L 表达。IL33 迅速诱导 MAPKs 和 IkappaBalpha 的磷酸化，并在 IL4 或 IFNgamma 预处理的细胞中增强炎症介质（IL6、IL8、IP-10、Gro-alpha、Gro-beta 和 MCP-1）的表达。IL33 刺激胰腺成肌纤维细胞的增殖和迁移。
IL33 及其受体复合物（ST2L 和 IL1RAcP）构成了一种新的信号系统，可能在慢性胰腺炎的发病机制中发挥重要作用。
