p38 mitogen-activated protein kinase is activated and linked to TNF-α signaling in inflammatory bowel disease
p38 mitogen-activated protein kinase is activated and linked to TNF-α signaling in inflammatory bowel disease
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DOI：
10.4049/jimmunol.168.10.5342
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发表时间：
2002-05-15
影响因子：
4.4
通讯作者：
Schreiber, S
中科院分区：
文献类型：
--
作者：
Waetzig, GH;Seegert, D;Schreiber, S
炎症性肠病(IBD)-克罗恩病和溃疡性结肠炎-是一种复发性慢性炎症性疾病，涉及遗传、免疫和环境因素。炎症性肠病炎症过程中的关键介质--肿瘤坏死因子-α的调节与丝裂原活化蛋白激酶通路密切相关。本研究的目的是研究4种p38亚型(p38α-Delta)、c-jun氨基末端蛋白(JNKs)和细胞外信号调节蛋白(ERK)1/2在炎症性肠黏膜中的活性和表达。Western印迹分析显示，p38α、JNKs和ERK1/2在1131)被显著激活，其中P38A表现出最显著的激酶活性增加。与正常对照组相比，IBD组p38和JNK蛋白表达仅有轻度改变，而ERK1/2蛋白表达显著下调。炎性粘膜活检免疫组织化学分析显示p38α主要表达于固有层巨噬细胞和中性粒细胞。对克罗恩病粘膜活检培养上清液的ELISA法筛选显示，与p38抑制剂SB 203580孵育可显著减少肿瘤坏死因子-α的分泌。体内单次注射抗肿瘤坏死因子-α单抗(英夫利昔单抗)抑制肿瘤坏死因子-α后，p38-α活性在注射后48小时内显著升高。在THP-1粒单核细胞中也观察到显著的英夫利昔单抗依赖的p38α激活。在人单核细胞中，英夫利昔单抗可促进肿瘤坏死因子-α基因的表达，这一作用可被SB 203580抑制。结论：p38α信号参与了IBD的病理生理过程。
Inflammatory bowel diseases (IBD)-Crohn's disease and ulcerative colitis-are relapsing chronic inflammatory disorders which involve genetic, immunological, and environmental factors. The regulation of TNF-alpha, a key mediator in the inflammatory process in IBD, is interconnected with mitogen-activated protein kinase pathways. The aim of this study was to characterize the activity and expression of the four p38 subtypes (p38alpha-delta), c-Jun N-terminal kinases (JNKs), and the extracellular signal-regulated kinases (ERK)1/2 in the inflamed intestinal mucosa. Western blot analysis revealed that p38alpha, JNKs, and ERK1/2 were significantly activated in 1131), with p38a showing the most pronounced increase in kinase activity. Protein expression of p38 and JNK was only moderately altered in IBD patients compared with normal controls, whereas ERK1/2 protein was significant) down-regulated. Immunohistochemical analysis of inflamed mucosal biopsies localized the main expression of p38alpha to lamina propria macrophages and neutrophils. ELISA screening of the supernatants of Crohn's disease mucosal biopsy cultures showed that incubation with the p38 inhibitor SB 203580 significantly reduced secretion of TNF-a. In vivo inhibition of TNF-alpha by a single infusion of anti-TNF-alpha Ab (infliximab) resulted in a highly significant transient increase of p38alpha activity during the first 48 h after infusion. A significant infliximab-dependent p38alpha activation was also observed in THP-1 myelomonocytic cells. In human monocytes, infliximab enhanced TNF-alpha gene expression, which could be inhibited by SB 203580. In conclusion, p38alpha signaling is involved in the pathophysiology of IBD.