Mascagni P, Sabbatini V, Biordi L, Martinotti S, Allegretti M, Marullo A, Caselli G, Bertini R
Dompé S.p.A., via Campo di Pile, 67100 L'Aquila, Italy.
Eur Cytokine Netw. 2000 Jun;11(2):185-92.
2-arylpropionic acids, a well known class of non-steroidal anti-inflammatory drugs (NSAIDs), exist as a racemic mixture of their enantiomeric forms, with S-isomers primarily responsible for inhibition of prostaglandin (PG) production and of inflammatory events. In this study we show that S-isomers are also responsible for the paradoxical up-regulation of tumor necrosis factor (TNF) induced by ketoprofen, flurbiprofen and ibuprofen in murine peritoneal macrophages stimulated by bacterial endotoxin (LPS). This effect is in close correlation with cyclooxygenase inhibitory capacity of S-isomers and, from Northern blot analysis, seems to be mediated by the up-regulation of TNF mRNA. In addition, up-regulation of TNF production by S-isomers is associated with inhibition of interleukin-10 (IL-10) production. Conversely, we have observed that S-enantiomers reduce IL-6 production at a concentration 100 times higher than that able to inhibit cyclooxygenase activity. The unwanted pro-inflammatory effects of S-isomers through TNF and IL-10 production could therefore hinder their analgesic effect, that is, at least in part, related to IL-6 inhibition. In addition, TNF amplification by S-isomers could be correlated to the clinical evidence of their gastric toxicity. On the other hand, R-isomers did not affect TNF and IL-10 production even at cyclooxygenase-blocking concentration, while they reduced IL-6 production to the same levels as S-isomers. It is concluded that the regulation of cytokine production by S-isomers of 2-arylpropionic acids could partially mask their therapeutic effects and could be correlated to the clinical evidence of their higher gastric toxicity. On the other hand, IL-6 inhibition without the unwanted effects on TNF and IL-10 production shown by R-isomers could be correlated to the analgesic effect reported for R-2-arylpropionic acids.
2-芳基丙酸是一类著名的非甾体抗炎药（NSAIDs），以对映体形式的外消旋混合物存在，其中S-异构体主要负责抑制前列腺素（PG）的产生和炎症反应。在本研究中，我们发现S-异构体还导致了酮洛芬、氟比洛芬和布洛芬在细菌内毒素（LPS）刺激的小鼠腹腔巨噬细胞中引起的肿瘤坏死因子（TNF）的反常上调。这种效应与S-异构体的环氧化酶抑制能力密切相关，并且从Northern印迹分析来看，似乎是由TNF mRNA的上调介导的。此外，S-异构体对TNF产生的上调与白细胞介素-10（IL-10）产生的抑制有关。相反，我们观察到S-对映体在比抑制环氧化酶活性高100倍的浓度下可降低IL-6的产生。因此，S-异构体通过TNF和IL-10产生的不良促炎作用可能会阻碍它们的镇痛效果，即至少部分与IL-6抑制有关。此外，S-异构体对TNF的放大作用可能与它们胃毒性的临床证据相关。另一方面，即使在环氧化酶阻断浓度下，R-异构体也不影响TNF和IL-10的产生，而它们将IL-6的产生降低到与S-异构体相同的水平。结论是，2-芳基丙酸的S-异构体对细胞因子产生的调节可能会部分掩盖它们的治疗效果，并且可能与它们更高胃毒性的临床证据相关。另一方面，R-异构体对TNF和IL-10产生没有不良影响的情况下对IL-6的抑制可能与报道的R-2-芳基丙酸的镇痛效果相关。
