Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFκB
Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFκB
复制标题
DOI：
10.1073/pnas.96.11.6377
复制
发表时间：
1999-05-25
影响因子：
11.1
通讯作者：
Weissmann, G
中科院分区：
文献类型：
--
作者：
Cronstein, BN;Montesinos, MC;Weissmann, G
阿司匹林的抗炎作用通常归因于直接抑制环氧化酶（COX-1和COX-2），但可能还有其他机制在起作用。这些包括阿司匹林抑制NF κ B向细胞核的易位，以及水杨酸盐解偶联氧化磷酸化（即消耗ATP）的能力。在临床相关剂量下，水杨酸盐引起细胞释放微摩尔浓度的腺苷，作为内源性配体，至少有四种不同类型的特征良好的受体。以前，我们已经证明腺苷介导其他有效的和广泛使用的抗炎药，甲氨蝶呤和磺胺嘧啶的抗炎作用，在体外和体内。确定体内是否临床相关的水杨酸法通过腺苷水平,通过NFκB,或通过“炎症”环氧酶cox - 2,我们研究了在通用的小鼠急性炎症air-pouch模型通过使用野生型老鼠和老鼠缺乏cox - 2或者施敏原著,呈现p50的前身,一个组件的multimeric转录因子NFκB,在这里,我们表明,阿司匹林和水杨酸钠的抗炎症作用,但不是糖皮质激素,在很大程度上是由抗炎类自身腺苷介导的，而不依赖于cox - 1或COX-2对前列腺素合成的抑制，也不依赖于p105的存在。事实上，阿司匹林和水杨酸钠的炎症和抗炎作用都独立于炎症部位的前列腺素水平。这些实验还提供了体内证实，糖皮质激素的抗炎作用部分取决于NF κ B的p105成分。
The antiinflammatory action of aspirin generally has been attributed to direct inhibition of cyclooxygenases (COX-1 and COX-2), but additional mechanisms are likely at work. These include aspirin's inhibition of NF kappa B translocation to the nucleus as well as the capacity of salicylates to uncouple oxidative phosphorylation (i.e., deplete ATP), At clinically relevant doses, salicylates cause cells to release micromolar concentrations of adenosine, which serves as an endogenous ligand far at least four different types of well-characterized receptors. Previously, we have shown that adenosine mediates the antiinflammatory effects of other potent and widely used antiinflammatory agents, methotrexate and sulfasalazine, both in vitro and in vivo. To determine in vivo whether clinically relevant levels of salicylate act via adenosine, via NF kappa B, or via the "inflammatory" cyclooxygenase COX-2, we studied acute inflammation in the generic murine air-pouch model by using wild-type mice and mice rendered deficient in either COX-2 or p105, the precursor of p50, one of the components of the multimeric transcription factor NF kappa B, Here, we show that the antiinflammatory effects of aspirin and sodium salicylate, but not glucocorticoids, are largely mediated by the antiinflammatory autacoid adenosine independently of inhibition of prostaglandin synthesis by COX-I or COX-2 or of the presence of p105, Indeed, both inflammation and the antiinflammatory effects of aspirin and sodium salicylate were independent of the levels of prostaglandins at the inflammatory site. These experiments also provide in vivo confirmation that the antiinflammatory effects of glucocorticoids depend, in part, on the p105 component of NF kappa B.