Adenine nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor
Adenine nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor
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DOI：
10.4049/jimmunol.173.12.7539
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发表时间：
2004-12-15
影响因子：
4.4
通讯作者：
Boyce, JA
中科院分区：
文献类型：
--
作者：
Feng, CL;Mery, AG;Boyce, JA
ATP和ADP激活功能不同的G蛋白偶联嘌呤能（P2Y）受体。我们确定的表达和功能的腺嘌呤核苷酸特异性P2Y受体对脐带血来源的人肥大细胞（hMCs）。人MC表达编码ADP特异性P2Y1、P2Y12和P2Y13受体、ATP/UTP特异性P2Y2受体和ATP选择性P2Y11受体的mRNA。ADP（0.05 - 50 μ M）诱导的钙流被P2Y1受体选择性拮抗剂完全阻断，并且不被ATP交叉脱敏。低剂量的ADP诱导ERK和p38 MAPK的强烈磷酸化;高剂量刺激类花生酸的产生和胞吐。尽管MAPK磷酸化被P2Y1-和P2Y12-选择性拮抗剂的组合阻断，但两者都不干扰分泌反应。出乎意料的是，ADP和ATP都抑制了响应于TLR2配体肽聚糖的TNF-α的产生，并阻断了响应于白三烯D-4的TNF-α、IL-8和MIP-1 β的产生。两种ATP类似物腺苷5'-O-（3-硫代三磷酸）和2'，3'-O-（4-苯甲酰基-苯甲酰基）腺苷5'-三磷酸（BzATP）模拟了这些作用，但腺苷没有。ADP、ATP、腺苷5'-O-（3-硫代三磷酸）和2'，3'-O-（4-苯甲酰基-苯甲酰基）腺苷5'-三磷酸均诱导cAMP积累，刺激CREB磷酸化，并上调诱导型cAMP早期阻遏物（CREB依赖性细胞因子转录抑制剂）的表达。因此，人MCs表达几种ADP选择性P2Y受体和至少一种G.偶联ADP/ATP受体。因此，核苷酸可能有助于MC依赖性微血管渗漏动脉粥样硬化，组织损伤，先天性免疫，同时限制了随后的炎症程度，通过减弱诱导细胞因子的生成MC。
ATP and ADP activate functionally distinct G protein-coupled purinergic (P2Y) receptors. We determined the expression and function of adenine nucleotide-specific P2Y receptors on cord blood-derived human mast cells (hMCs). Human MCs expressed mRNA encoding the ADP-specific P2Y1, P2Y12, and P2Y13 receptors; the ATP/UTP-specific P2Y2 receptor; and the ATP-selective P2Y11 receptor. ADP (0.05-50 muM) induced calcium flux that was completely blocked by a P2Y1 receptor-selective antagonist and was not cross-desensitized by ATP. Low doses of ADP induced strong phosphorylation of ERK and p38 MAPKs; higher doses stimulated eicosanoid production and exocytosis. Although MAPK phosphorylation was blocked by a combination of P2Y1- and P2Y12-selective antagonists, neither interfered with secretion responses. Unexpectedly, both ADP and ATP inhibited the generation of TNF-alpha in response to the TLR2 ligand, peptidoglycan, and blocked the production of TNF-alpha, IL-8, and MIP-1beta in response to leukotriene D-4. These effects were mimicked by two ATP analogues, adenosine 5'-O-(3-thiotriphosphate) and 2',3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate (BzATP), but not by adenosine. ADP, ATP, adenosine 5'-O-(3-thiotriphosphate), and 2',3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate each induced cAMP accumulation, stimulated the phosphorylation of CREB, and up-regulated the expression of inducible cAMP early repressor, a CREB-dependent inhibitor of cytokine transcription. Human MCs thus express several ADP-selective P2Y receptors and at least one G.-coupled ADP/ATP receptor. Nucleotides could therefore contribute to MC-dependent microvascular leakage in atherosclerosis, tissue injury, and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs.