A specific inhibitor of the p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: Dependence on CD28 signaling and preferential inhibition of IL-10 production
A specific inhibitor of the p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: Dependence on CD28 signaling and preferential inhibition of IL-10 production
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DOI：
10.1006/cimm.1998.1448
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发表时间：
1999-03-15
影响因子：
4.3
通讯作者：
Dumont, FJ
中科院分区：
文献类型：
--
作者：
Koprak, S;Staruch, MJ;Dumont, FJ
T细胞活化时产生的细胞因子是TCR/CD3和CD28等共刺激分子等多种信号通路整合的结果。在这些通路中，p38丝裂原活化蛋白激酶(MAPK)的可能作用最不为人所知。在这里，我们使用一种高度特异的p38 MAPK抑制剂，SB203580化合物，来检测该酶在抗CD3和抗CD28单抗联合或与PMA联合刺激人T细胞产生各种细胞因子中的作用。用ELISA法和在mRNA水平上监测细胞因子的诱导。而SB203580对IL-2的产生和增殖影响不大，但显著减少了其他几种细胞因子的产生，IL-4、IL-5、IL-13和TNF-α的分泌被抑制20-50%，其T细胞激活方式涉及CD28途径，但对它们的mRNA表达影响不大。相反，通过CD28/PMA或CD3/CD28诱导的干扰素-γ在蛋白和mRNA水平上均显著降低，最有趣的是，SB203580还通过依赖CD28的激活抑制IL-10的分泌和mRNA的诱导达75-85%(IC50与0.2mM相似)。亚群分析表明，这种抑制并不反映对T细胞亚群的不同影响。因此，p38MAPK活性似乎有助于细胞因子的产生，主要是通过CD28依赖的信号转导，此外，IL-10似乎比其他细胞因子更依赖于这一活性来诱导T细胞。(C)1999年学术出版社。
Cytokine production upon T cell activation results from the integration of multiple signaling pathways from TCR/CD3 and from costimulatory molecules such as CD28. Among these pathways, the possible role of p38 mitogen activated protein kinase (MAPK) is the least understood. Here, we used a highly specific p38 MAPK inhibitor, the SB203580 compound, to examine the role of this enzyme in the induction of various cytokines in human T cells stimulated with anti-CD3 and anti-CD28 mAb together or in combination with PMA. Cytokine induction was monitored by ELISA and at the mRNA level. While SB203580 had little effect on IL-2 production and proliferation, it significantly reduced the production of several other cytokines, The secretion of IL-4, IL-5, IL-13, and TNF-alpha was inhibited by 20-50% with modes of T cell activation involving the CD28 pathway, whereas their mRNA expression was little affected. In contrast, IFN-gamma induction via CD28/PMA or CD3/CD28, but not CD3/PMA, was markedly diminished both at the protein and at the mRNA levels, Most interestingly, SB203580 also sup pressed IL-10 secretion and mRNA induction via CD28-dependent activation by 75-85% (IC50 similar to 0.2 mu M). Subset analysis suggested that this inhibition did not reflect a differential effect on T cell subsets. Therefore, p38 MAPK activity appears to contribute to cytokine production, mostly via CD28-dependent signaling, Moreover, IL-10 seems to rely more on this activity than other cytokines for its induction in T cells. (C) 1999 Academic Press.