Suppression of inflammation by low-dose methotrexate is mediated by adenosine A2A receptor but not A3 receptor activation in thioglycollate-induced peritonitis.
Suppression of inflammation by low-dose methotrexate is mediated by adenosine A2A receptor but not A3 receptor activation in thioglycollate-induced peritonitis.
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DOI：
10.1186/ar1914
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发表时间：
2006
影响因子：
4.9
通讯作者：
Cronstein BN
中科院分区：
文献类型：
--
作者：
Montesinos MC;Desai A;Cronstein BN
先前的研究表明，腺苷，作用于一个或多个其受体，介导甲氨蝶呤在急性和慢性炎症的动物模型中的抗炎作用。腺苷A2 A和A3受体都有助于甲氨蝶呤治疗在气囊炎症模型中的抗炎作用，并且这两种受体对炎症的调节在细胞水平上不同。由于不同的因素可能调节不同部位的炎症，我们在腺苷A2 A受体敲除小鼠和A3受体敲除小鼠及其野生型同窝仔的急性腹膜炎症模型中检查了低剂量每周甲氨蝶呤治疗（0.75 mg/kg/周）的效果。腹腔注射巯基乙酸盐后，腺苷A2 A敲除小鼠或野生型对照小鼠中巯基乙酸盐诱导的腹膜渗出液中蓄积的白细胞数量或类型、肿瘤坏死因子α（TNF-α）和IL-10水平无显著差异。相反，腺苷A3受体缺陷小鼠的渗出液中有更多的白细胞、TNF-α和IL-10。低剂量，每周甲氨蝶呤治疗增加了所有研究小鼠腹腔渗出液中的腺苷浓度，并减少了野生型小鼠和A3受体敲除小鼠中的白细胞蓄积，但在A2 A受体敲除小鼠中没有。甲氨蝶呤降低了野生型小鼠和A3受体敲除小鼠的TNF-α渗出水平，但对A2 A受体敲除小鼠无影响。更引人注目的是，IL-10，腹膜炎症的关键调节因子，在蛋氨酸治疗的野生型小鼠和A3基因敲除小鼠中增加，但在A2 A基因敲除小鼠中减少。地塞米松是一种通过不同机制抑制炎症的药物，在野生型小鼠、A2 A小鼠和A3基因敲除小鼠中同样有效。这些发现提供了进一步的证据，腺苷是一种有效的炎症调节剂，介导甲氨蝶呤的抗炎作用。此外，这些数据提供了强有力的证据表明，甲氨蝶呤和腺苷的抗炎作用是由不同炎症部位的不同受体介导的，这一观察结果可以解释为什么某些器官的炎性疾病对甲氨蝶呤治疗有反应，而其他器官则无反应。
Prior studies demonstrate that adenosine, acting at one or more of its receptors, mediates the anti-inflammatory effects of methotrexate in animal models of both acute and chronic inflammation. Both adenosine A2A and A3 receptors contribute to the anti-inflammatory effects of methotrexate treatment in the air pouch model of inflammation, and the regulation of inflammation by these two receptors differs at the cellular level. Because different factors may regulate inflammation at different sites we examined the effect of low-dose weekly methotrexate treatment (0.75 mg/kg/week) in a model of acute peritoneal inflammation in adenosine A2A receptor knockout mice and A3 receptor knockout mice and their wild-type littermates. Following intraperitoneal injection of thioglycollate there was no significant difference in the number or type of leukocytes, tumor necrosis factor alpha (TNF-α) and IL-10 levels that accumulated in the thioglycollate-induced peritoneal exudates in adenosine A2A knockout mice or wild-type control mice. In contrast, there were more leukocytes, TNF-α and IL-10 in the exudates of the adenosine A3 receptor-deficient mice. Low-dose, weekly methotrexate treatment increased the adenosine concentration in the peritoneal exudates of all mice studied, and reduced the leukocyte accumulation in the wild-type mice and A3 receptor knockout mice but not in the A2A receptor knockout mice. Methotrexate reduced exudate levels of TNF-α in the wild-type mice and A3 receptor knockout mice but not the A2A receptor knockout mice. More strikingly, IL-10, a critical regulator of peritoneal inflammation, was increased in the methotrexate-treated wild-type mice and A3 knockout mice but decreased in the A2A knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was similarly effective in wild-type mice, A2A mice and A3 knockout mice. These findings provide further evidence that adenosine is a potent regulator of inflammation that mediates the anti-inflammatory effects of methotrexate. Moreover, these data provide strong evidence that the anti-inflammatory effects of methotrexate and adenosine are mediated by different receptors in different inflammatory loci, an observation that may explain why inflammatory diseases of some organs but not of other organs respond to methotrexate therapy.
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DOI：
10.1006/bbrc.1999.0196
发表时间：
1999-02-16
影响因子：
3.1
作者：
Ajuebor, MN;Das, AM;Perretti, M
通讯作者：
Perretti, M
影响因子：
6.7
作者：
LACKI, JK;KLAMA, K;MULLER, W
通讯作者：
MULLER, W
影响因子：
20.1
作者：
Feoktistov, I;Goldstein, AE;Biaggioni, I
通讯作者：
Biaggioni, I
影响因子：
15.9
作者：
Bong, GW;Rosengren, S;Firestein, GS
通讯作者：
Firestein, GS
影响因子：
3.6
作者：
Desai, A;Victor-Vega, C;Cronstein, BN
通讯作者：
Cronstein, BN