Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse
Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse
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DOI：
10.1172/jci200113640
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发表时间：
2001-10-01
影响因子：
15.9
通讯作者：
Coffman, TM
中科院分区：
文献类型：
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作者：
Nataraj, C;Thomas, DW;Coffman, TM
前列腺素E-2（PGE（2））的产生在炎症过程中增强，这种脂质介质可以显着调节免疫反应。有四种PGE（2）受体（EP 1-EP 4），具有独特的表达模式和与细胞内信号传导途径的不同偶联。为了鉴定调节细胞免疫反应的EP受体，我们使用了小鼠品系，其中编码四种EP受体中的每一种的基因通过基因靶向被破坏。使用混合淋巴细胞反应（MLR）作为细胞免疫反应的模型，我们证实了PGE（2）对野生型应答细胞具有有效的抗增殖作用。EP 1或EP 3受体的缺失并不改变MLR中对PGE（2）的抑制反应。相反，当反应细胞缺乏EP 2受体时，PGE（2）对增殖几乎没有影响。在EP 4（-/-）应答细胞中也观察到对PGE（2）的适度抗性。重建实验表明，EP 2受体主要通过直接作用于T细胞来抑制MLR。此外，PGE（2）通过激活EN受体从而抑制细胞因子释放来调节巨噬细胞功能。因此，PGE（2）通过不同免疫细胞群体上的不同EP受体调节细胞免疫应答：EP 2受体直接抑制T细胞增殖，而EP 2和EP 4受体调节抗原呈递细胞功能。
Production of prostaglandin E-2 (PGE(2)) is enhanced during inflammation, and this Lipid mediator can dramatically modulate immune responses. There are four receptors for PGE(2) (EP1-EP4) with unique patterns of expression and different coupling to intracellular signaling pathways. To identify the EP receptors that regulate cellular immune responses, we used mouse lines in which the genes encoding each of the four EP receptors were disrupted by gene targeting. Using the mixed lymphocyte response (MLR) as a model cellular immune response, we confirmed that PGE(2) has potent antiproliferative effects on wild-type responder cells. The absence of either the EP1 or EP3 receptors did not alter the inhibitory response to PGE(2) in the MLR. In contrast, when responder cells lacked the EP2 receptor, PGE(2) had little effect on proliferation. Modest resistance to PGE(2) was also observed in EP4(-/-) responder cells. Reconstitution experiments suggest that EP2 receptors primarily inhibit the MLR through direct actions on T cells. Furthermore, PGE(2) modulates macrophage function by activating the EN receptor and thereby inhibiting cytokine release. Thus, PGE(2) regulates cellular immune responses through distinct EP receptors on different immune cell populations: EP2 receptors directly inhibit T cell proliferation while EP2 and EP4 receptors regulate antigen presenting cells functions.