Infliximab and the TNF-α system
Infliximab and the TNF-α system
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DOI：
10.1152/ajpgi.90576.2008
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发表时间：
2009-03-01
影响因子：
4.5
通讯作者：
Ebert, Ellen C.
中科院分区：
文献类型：
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作者：
Ebert, Ellen C.
埃伯特EC.英夫利西单抗和TNF-α系统。美国生理学杂志胃肠和肝脏生理学296：G612-G620，2009年。首次发表于2009年1月8日; doi：10.1152/ajpgi.90576.2008。英夫利昔单抗是一种抗TNF-α的嵌合单克隆抗体，对克罗恩病（CD）和类风湿性关节炎（RA）有效。其主要作用机制被认为是诱导细胞凋亡。本研究使用正常个体和CD、溃疡性结肠炎和RA患者的外周血单核细胞和T细胞以及固有层淋巴细胞，详细评估英夫利西单抗对TNF-α系统的影响。在不存在可能掩盖细微发现的强刺激的情况下，在静息状态下研究淋巴细胞。英夫利西单抗没有改变活细胞的数量。相反，它导致单核细胞增加可溶性TNFR 2的释放，可溶性TNFR 2用于中和TNF-α，增强英夫利昔单抗的作用。它减少TNFR 2表达，从而降低TNF-α反应性。这些变化是由于TNFR 2的产生上调，而不是脱落增加。英夫利西单抗没有引起TNF-α转录本的反弹产生，这将抵消其作用。它特异性地增强白细胞分泌的IL-10的产生，但不增强促炎细胞因子的产生，从而促进抗炎微环境。此外，英夫利西单抗引起单核细胞c-Jun氨基末端激酶磷酸化升高。因此，英夫利西单抗操纵TNF-α系统以促进其抗TNF-α作用。
Ebert EC. Infliximab and the TNF-alpha system. Am J Physiol Gastrointest Liver Physiol 296: G612-G620, 2009. First published January 8, 2009; doi:10.1152/ajpgi.90576.2008.-Infliximab, a chimeric monoclonal antibody against TNF-alpha, is efficacious in Crohn's disease (CD) and rheumatoid arthritis (RA). Its main mechanism of action is thought to be the induction of apoptosis. The present study evaluates in detail the effects of infliximab on the TNF-alpha system using peripheral blood monocytes and T cells as well as lamina propria lymphocytes from normal individuals and patients with CD, ulcerative colitis, and RA. Lymphocytes were studied in the resting state in the absence of strong stimuli that may obscure subtle findings. Infliximab did not change the numbers of viable cells. Rather, it caused monocytes to increase their release of soluble TNFR2, which serves to neutralize TNF-alpha, potentiating the action of infliximab. It reduced TNFR2 expression, thereby decreasing TNF-alpha responsiveness. These changes were due to upregulated production of TNFR2 rather than increased shedding. Infliximab did not cause rebound production of TNF-alpha transcripts that would counteract its effects. It specifically enhanced production of IL-10 but not proinflammatory cytokines secreted by leukocytes, thereby promoting an anti-inflammatory microenvironment. In addition, infliximab caused a rise in c-Jun amino-terminal kinase phosphorylation by monocytes. Thus infliximab manipulates the TNF-alpha system to promote its anti-TNF-alpha effects.