Gómez-Gaviro María Victoria, González-Alvaro Isidoro, Domínguez-Jiménez Carmen, Peschon Jacques, Black Roy A, Sánchez-Madrid Francisco, Díaz-González Federico
Servicio de Reumatologia, Hospital de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, Madrid 28006, Spain.
J Biol Chem. 2002 Oct 11;277(41):38212-21. doi: 10.1074/jbc.M205142200. Epub 2002 Jul 29.
It has been recently described that some non-steroidal anti-inflammatory drugs (NSAIDs) are able to induce the shedding of L-selectin in neutrophils, an adhesion molecule that plays an essential role in the inflammatory response. We have found that, according to this capability, NSAIDs could be grouped into three categories. A high releaser group (flufenamic, meclofenamic, and mefenamic acids, diclofenac and aceclofenac), a group of moderate releasers (aspirin, indomethacin, nimesulide, flurbiprofen, and ketoprofen), and a non-releaser group (phenylbutazone and the oxicams, piroxicam and meloxicam). Only NSAIDs from the high releaser group shared diphenylamine in their chemical structure. The amine group of this chemical agent proved to be essential for the anti-L-selectin activity of diphenylamine-based NSAIDs. The presence of a carboxylic acid group in the diphenylamine (N-phenylanthranilic acid) highly increased its ability to reduce the L-selectin surface expression in neutrophils. Diphenylamine and N-phenylanthranilic acid neither affected COX activity in platelets nor modified the activation state of neutrophils. Diphenylamine-related compounds, which include the diphenylamine-based NSAIDs caused a variable reduction in the neutrophil intracellular ATP concentration, which correlated with the differential ability of such compounds to trigger L-selectin shedding (r = 0.97, p < 0.01). Diphenylamine-related compounds failed to down-regulate L-selectin in a tumor necrosis factor-alpha-converting enzyme (TACE)-deficient murine monocytic cell line. Our data indicate that diphenylamine seems to be the structural core of NSAIDs accounting for their down-regulatory activity of L-selectin leukocyte expression. Diphenylamine and its related compounds exert this action on L-selectin through a prostaglandin-independent, TACE-dependent mechanism that seems to be linked to the capability of these agents to uncouple the mitochondrial oxidative phosphorylation.
最近有研究表明，一些非甾体抗炎药（NSAIDs）能够诱导中性粒细胞中L-选择素的脱落，L-选择素是一种在炎症反应中起重要作用的黏附分子。我们发现，根据这种能力，NSAIDs可分为三类。高释放剂组（氟芬那酸、甲氯芬那酸、甲芬那酸、双氯芬酸和醋氯芬酸）、中度释放剂组（阿司匹林、吲哚美辛、尼美舒利、氟比洛芬和酮洛芬）和非释放剂组（保泰松和昔康类，吡罗昔康和美洛昔康）。只有高释放剂组的NSAIDs在其化学结构中含有二苯胺。这种化学试剂的胺基被证明是基于二苯胺的NSAIDs抗L-选择素活性所必需的。二苯胺（N-苯基邻氨基苯甲酸）中羧酸基团的存在极大地提高了其降低中性粒细胞表面L-选择素表达的能力。二苯胺和N-苯基邻氨基苯甲酸既不影响血小板中的COX活性，也不改变中性粒细胞的激活状态。与二苯胺相关的化合物，包括基于二苯胺的NSAIDs，会导致中性粒细胞内ATP浓度不同程度的降低，这与这些化合物引发L-选择素脱落的不同能力相关（r = 0.97，p < 0.01）。与二苯胺相关的化合物在肿瘤坏死因子-α转换酶（TACE）缺陷的小鼠单核细胞系中未能下调L-选择素。我们的数据表明，二苯胺似乎是NSAIDs的结构核心，这解释了它们对L-选择素白细胞表达的下调活性。二苯胺及其相关化合物通过一种不依赖前列腺素、依赖TACE的机制对L-选择素发挥这种作用，这种机制似乎与这些药物解偶联线粒体氧化磷酸化的能力有关。
