Prostaglandin E2 Inhibits NLRP3 Inflammasome Activation through EP4 Receptor and Intracellular Cyclic AMP in Human Macrophages.
Prostaglandin E2 Inhibits NLRP3 Inflammasome Activation through EP4 Receptor and Intracellular Cyclic AMP in Human Macrophages.
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DOI：
10.4049/jimmunol.1401343
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发表时间：
2015-06-01
期刊：
影响因子：
--
通讯作者：
Shelhamer JH
中科院分区：
文献类型：
--
作者：
Sokolowska M;Chen LY;Liu Y;Martinez-Anton A;Qi HY;Logun C;Alsaaty S;Park YH;Kastner DL;Chae JJ;Shelhamer JH
前列腺素E_2(PGE_2)是一种有效的脂质介质，参与维持体内平衡，但也促进慢性炎症和癌症的急性炎症或免疫抑制。NLRP3炎症体在宿主防御中起重要作用。由于NLRP3基因突变导致NLRP3炎症体的不受控制的激活，会导致低温比林相关的周期性综合征(CAPS)。在这里，我们发现PGE2抑制了人原代单核细胞来源的巨噬细胞中NLRP3炎症体的激活。这种作用是通过前列腺素E受体4(EP4)和细胞内cAMP的增加而实现的，这种作用不依赖于蛋白激酶A(PKA)或由cAMP直接激活的交换蛋白(EPAC)。EP4的特异性激动剂模拟，而其拮抗剂或EP4被击倒则逆转PGE2介导的NLRP3抑制。PGE2使细胞内cAMP升高。腺苷环化酶抑制剂阻断PGE2对NLRP3的抑制作用。腺苷环化酶激活剂或cAMP类似物增加细胞内cAMP，或磷酸二酯酶抑制剂阻断cAMP降解，均可降低NLRP3的活性。PKA或EPAC激动剂不能模拟，它们的拮抗剂也不能逆转PGE2介导的NLRP3抑制。此外，高剂量的前列腺素E_2显著降低了脂多糖刺激的CAPS患者外周血单核细胞的结构性IL-1β的分泌。此外，用胞浆磷脂酶A2α抑制剂或小干扰RNA阻断胞浆磷脂酶A2或抑制环氧合酶2，从而抑制内源性前列腺素E_2的产生，可增加NLRP3炎症体的激活。我们的结果提示，PGE2可能在炎症消退阶段发挥维持体内平衡的作用，并可能作为自分泌和旁分泌调节因子。
Prostaglandin E2 (PGE2) is a potent lipid mediator involved in maintaining homeostasis but also promotion of acute inflammation or immune suppression in chronic inflammation and cancer. NLRP3 inflammasome plays an important role in host defense. Uncontrolled activation of NLRP3 inflammasome, due to mutations in the NLRP3 gene causes cryopyrin-associated periodic syndromes (CAPS). Here, we showed that NLRP3 inflammasome activation is inhibited by PGE2 in human primary monocyte-derived macrophages. This effect was mediated through prostaglandin E receptor 4 (EP4) and an increase in intracellular cAMP, independently of protein kinase A (PKA) or exchange protein directly activated by cAMP (Epac). A specific agonist of EP4 mimicked, while its antagonist or EP4 knockdown reversed PGE2-mediated NLRP3 inhibition. PGE2 caused an increase in intracellular cAMP. Blockade of adenylate cyclase by its inhibitor reversed PGE2-mediated NLRP3 inhibition. Increase of intracellular cAMP by an activator of adenylate cyclase or an analog of cAMP, or a blockade of cAMP degradation by phosphodiesterase inhibitor decreased NLRP3 activation. PKA or Epac agonists did not mimic and their antagonists did not reverse PGE2-mediated NLRP3 inhibition. In addition, constitutive IL-1β secretion from LPS-primed PBMCs of CAPS patients was substantially reduced by high doses of PGE2. Moreover, blocking cytosolic phospholipase A2α by its inhibitor or siRNA or inhibiting cyclooxygenase 2, resulting in inhibition of endogenous PGE2 production, caused an increase in NLRP3 inflammasome activation. Our results suggest that PGE2 might play a role in maintaining homeostasis during the resolution phase of inflammation and might serve as an autocrine and paracrine regulator.
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影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.050585197
发表时间：
2000-03-28
影响因子：
11.1
作者：
Fawcett, L;Baxendale, R;Phillips, SC
通讯作者：
Phillips, SC
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1084/jem.20100050
发表时间：
2010-05-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Allen IC;TeKippe EM;Woodford RM;Uronis JM;Holl EK;Rogers AB;Herfarth HH;Jobin C;Ting JP
通讯作者：
Ting JP