Adenosine inhibits tumor necrosis factor-α release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor
Adenosine inhibits tumor necrosis factor-α release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor
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DOI：
10.1124/jpet.105.096016
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发表时间：
2006-04-01
影响因子：
3.5
通讯作者：
Auchampach, JA
中科院分区：
文献类型：
--
作者：
Kreckler, LM;Wan, TC;Auchampach, JA
腺苷在受损组织中被加工，在那里它抑制基本上所有免疫细胞的炎症反应，包括促炎细胞因子如肿瘤坏死因子-α（TNF-α）的产生。腺苷的大多数抗炎作用归因于通过A（2A）腺苷受体（A（2A）AR）的信号传导。然而，先前已经显示，A（3）AR激动剂N-6-（3-碘苄基）腺苷-5 '-N-甲基甲酰胺（IB-MECA）有效地抑制从A（2A）AR "敲除"（A（2A）KO）小鼠获得的巨噬细胞释放TNF-α，这表明A（3）AR也可以调节细胞因子表达。在这里，我们证实A（2A）AR是抑制Toll样受体依赖性（TLR）和TLR非依赖性刺激诱导的巯基乙酸盐诱导的小鼠腹腔巨噬细胞释放TNF-α的主要AR亚型，但我们确定A（2B）AR而不是A（3）AR介导腺苷的非A（2A）AR作用，因为1）IB-MECA抑制TNF-α的能力，α释放在从A3 KO小鼠分离的巨噬细胞中没有改变，和2）A（2B）AR拮抗剂1，3-二丙基-8-[4-[（（4-氰基苯基）氨甲酰基甲基）氧基]苯基]黄嘌呤（MRS 1754）阻断非选择性AR激动剂腺苷-5 '-N-乙基甲酰胺（NECA）抑制TNF-α的能力。从分离自A（2A）KO小鼠的巨噬细胞释放α。尽管A（2B）AR：似乎能够抑制TNF-α释放，但A（2A）AR起主要抑制作用，因为MRS 1754不能阻断NECA抑制从野生型（WT）小鼠分离的巨噬细胞释放TNF-α的能力。此外，腺苷抑制WT巨噬细胞释放TNF-α的效力和功效不受MRS 1754阻断A（2B）AR的影响。数据表明，腺苷主要通过A（2A）AR抑制巨噬细胞释放TNF-α，尽管A 2B AR似乎发挥潜在的抑制作用，可能有助于腺苷在特定情况下的抗炎作用。
Adenosine is elaborated in injured tissues where it suppresses inflammatory responses of essentially all immune cells, including production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha). Most of the anti-inflammatory actions of adenosine have been attributed to signaling through the A(2A) adenosine receptor (A(2A)AR). Previously, however, it has been shown that the A(3)AR agonist N-6-(3-iodobenzyl)adenosine-5' -N-methylcarboxamide (IB-MECA) potently inhibited TNF-alpha release from macrophages obtained from A(2A)AR "knockout" (A(2A)KO) mice, suggesting that the A(3)AR may also regulate cytokine expression. Here, we confirmed that the A(2A)AR is the primary AR subtype that suppresses TNF-alpha release from thioglycollate-elicited mouse peritoneal macrophages induced by both Toll-like receptor-dependent (TLR) and TLR-independent stimuli, but we determined that the A(2B)AR rather than the A(3)AR mediates the non-A(2A)AR actions of adenosine since 1) the ability of IB-MECA to inhibit TNF-alpha release was not altered in macrophages isolated from A 3 KO mice, and 2) the A(2B)AR antagonist 1,3-dipropyl- 8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]xanthine (MRS 1754) blocked the ability of the nonselective AR agonist adenosine-5' -N-ethylcarboxamide (NECA) to inhibit TNF-alpha release from macrophages isolated from A(2A)KO mice. Although A(2B)ARs :seem capable of inhibiting TNF-alpha release, the A(2A)AR plays a dominant suppressive role since MRS 1754 did not block the ability of NECA to inhibit TNF-alpha release from macrophages isolated from wild-type (WT) mice. Furthermore, the potency and efficacy of adenosine to inhibit TNF-alpha release from WT macrophages were not influenced by blocking A(2B)ARs with MRS 1754. The data indicate that adenosine suppresses TNF-alpha release from macrophages primarily via A(2A)ARs, although the A 2B AR seems to play an underlying inhibitory role that may contribute to the anti-inflammatory actions of adenosine under select circumstances.