Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease
Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease
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DOI：
10.1111/j.1365-2249.2010.04203.x
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发表时间：
2010-10-01
影响因子：
4.6
通讯作者：
MacDonald, T. T.
中科院分区：
文献类型：
--
作者：
Docena, G.;Rovedatti, L.;MacDonald, T. T.
克罗恩病和溃疡性结肠炎是炎症性肠病（IBD），以慢性复发性粘膜炎症为特征。肿瘤坏死因子(TNF)- α是一种已知的丝裂原活化蛋白激酶（MAPK）途径的激动剂，是该过程中的关键细胞因子。我们的目的首先是确定p38 MAPK是否在IBD炎症粘膜中被激活，然后研究四种不同的p38 α抑制化合物对IBD固有层单个核细胞（LPMCs）和器官培养活检中MAPK磷酸化和促炎细胞因子分泌的影响。通过免疫印迹法对克罗恩病和溃疡性结肠炎患者的炎症区以及性别和年龄匹配的对照组的正常粘膜进行肠道活检，评估体内磷酸化-p38 α和p38 α的表达。粘膜活检和分离的lpmc均与四种不同的p38 α选择性抑制药物孵育。采用酶联免疫吸附法测定器官和细胞培养上清中的tnf - α、白细胞介素(IL)-1 β和IL-6。我们发现，与对照组相比，IBD患者炎症粘膜中磷酸化p38 α的水平更高。所有p38 α抑制药物均抑制IBD lpmc和活检中p38 α磷酸化和tnf - α、IL-1 β和IL-6的分泌。激活的p38 α MAPK在IBD患者的炎症粘膜中上调。此外，所有p38 α选择性抑制药物均显著下调MAPK通路的激活和促炎细胞因子的分泌。
P>Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)-alpha, a known agonist of the mitogen-activated protein kinase (MAPK) pathway, is a key cytokine in this process. We aimed first to determine whether p38 MAPK is activated in IBD inflamed mucosa, and then studied the effect of four different p38 alpha inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies. In vivo phospho-p38 alpha and p38 alpha expression was evaluated by immunoblotting on intestinal biopsies from inflamed areas of patients affected by Crohn's disease and ulcerative colitis, and from normal mucosa of sex- and age-matched control subjects. Both mucosal biopsies and isolated LPMCs were incubated with four different p38 alpha selective inhibitory drugs. TNF-alpha, interleukin (IL)-1 beta and IL-6 were measured in the organ and cell culture supernatants by enzyme-linked immunosorbent assay. We found higher levels of phospho-p38 alpha in the inflamed mucosa of IBD patients in comparison to controls. All the p38 alpha inhibitory drugs inhibited p38 alpha phosphorylation and secretion of TNF-alpha, IL-1 beta and IL-6 from IBD LPMCs and biopsies. Activated p38 alpha MAPK is up-regulated in the inflamed mucosa of patients with IBD. Additionally, all the p38 alpha selective inhibitory drugs significantly down-regulated the activation of the MAPK pathway and the secretion of proinflammatory cytokines.