TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells
TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells
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DOI：
10.1038/cdd.2008.128
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发表时间：
2008-09
影响因子：
12.4
通讯作者：
Ricardo Weinlich;K. Bortoluci;C. F. Chehab;C. H. Serezani;A. G. Ulbrich;Marc Peters-Golden;Momtchilo Russo;G. Amarante-Mendes
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文献类型：
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作者：
Ricardo Weinlich;K. Bortoluci;C. F. Chehab;C. H. Serezani;A. G. Ulbrich;Marc Peters-Golden;Momtchilo Russo;G. Amarante-Mendes
抗原呈递细胞（APC）通过多种机制控制T细胞应答，包括共刺激分子的表达和控制T细胞增殖、存活和分化的细胞因子和其他介质的产生。在这里，我们证明了Toll样受体（TLR）激活的APC产生的可溶性因子抑制激活诱导的细胞死亡（AICD）。这种效应在未刺激的APC中观察到，但在脂多糖（LPS）处理后显著增加。使用不同的KO小鼠，我们发现LPS诱导的保护因子依赖于TLR 4/MyD 88。我们确定了保护因子为前列腺素E2（PGE 2），并表明APC衍生的上清液和PGE 2都阻止了T细胞对TCR/CD 3刺激的CD 95 L上调，从而避免了AICD和活化的T细胞对靶巨噬细胞的杀伤。PGE 2受体EP 2和EP 4似乎参与其中，因为这些受体的药理学刺激模拟对T细胞的保护作用，并且它们各自的拮抗剂干扰由APC衍生的或合成的PGE 2诱导的保护。最后，EP 2和EP 4的参与协同激活蛋白激酶A（PKA）和由cAMP途径直接激活的交换蛋白，以防止AICD。综上所述，这些结果表明，APC可以通过TLR 4/MyD 88依赖性途径响应于LPS释放PGE 2来调节T细胞的CD 95 L水平，从而影响T细胞及其自身的存活。
Antigen-presenting cells (APCs) control T-cell responses by multiple mechanisms, including the expression of co-stimulatory molecules and the production of cytokines and other mediators that control T-cell proliferation, survival and differentiation. Here, we demonstrate that soluble factor (s) produced by Toll-like receptor (TLR)-activated APCs suppress activation-induced cell death (AICD). This effect was observed in non-stimulated APCs, but it was significantly increased after lipopolysaccharide (LPS) treatment. Using different KO mice, we found that the LPS-induced protective factor is dependent on TLR4/MyD88. We identified the protective factor as prostaglandin E 2 (PGE 2) and showed that both APC-derived supernatants and PGE 2 prevented CD95L upregulation in T cells in response to TCR/CD3 stimulation, thereby avoiding both AICD and activated T cell killing of target macrophages. The PGE 2 receptors, EP2 and EP4, appear to be involved since pharmacological stimulation of these receptors mimics the protective effect on T cells and their respective antagonists interfere with the protection induced by either APCs derived or synthetic PGE 2. Finally, the engagement of EP2 and EP4 synergistically activates protein kinase A (PKA) and exchange protein directly activated by cAMP pathways to prevent AICD. Taken together, these results indicate that APCs can regulate T-cell levels of CD95L by releasing PGE 2 in response to LPS through a TLR4/MyD88-dependent pathway, with consequences for both T cell and their own survival.