Prabhakar U, Lipshutz D, Truneh A
Department of Cellular Biochemistry and Immunology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Int J Immunopharmacol. 1993 Feb;15(2):205-9. doi: 10.1016/0192-0561(93)90096-h.
Compounds from two distinct pharmacological classes namely, SK&F 86002 and pentoxifylline, were examined for their effects on TNF alpha and IL-1 beta release by human monocytes stimulated with LPS or monoclonal antibodies to three cell surface glycoproteins, CD44, CD45 and LFA-3 (LFA-3 is also known as CD58). SK&F 86002, an inhibitor of 5-LO and CO in arachidonic acid metabolism, inhibited LPS-induced release of TNF alpha and IL-1 beta with an IC50 of 1 microM. At this dose, it also inhibited by > 50%, release of both cytokines induced by the three monoclonal antibodies. Pentoxifylline, a methylxanthine derivative with phosphodiesterase inhibitory activity, selectively inhibited LPS-induced TNF alpha release with an IC50 of 100 microM. TNF alpha and IL-1 beta release mediated by the monoclonal antibodies were inhibited by less than 30% in the presence of 100 microM pentoxifylline. These results suggest that (a) LPS induced cytokine release shares a common step with the physiologically relevant stimuli (involving cross-linking of cell surface receptors), and that this pathway is sensitive to inhibition by SK&F 86002 and, (b) SK&F 86002 is more potent than pentoxifylline in inhibiting TNF alpha and IL-1 beta release induced by both stimuli.
研究了来自两个不同药理学类别的化合物，即SK&F 86002和己酮可可碱，观察它们对脂多糖（LPS）或针对三种细胞表面糖蛋白（CD44、CD45和淋巴细胞功能相关抗原3（LFA-3，也称为CD58））的单克隆抗体刺激的人单核细胞释放肿瘤坏死因子α（TNFα）和白细胞介素-1β（IL-1β）的影响。SK&F 86002是花生四烯酸代谢中5-脂氧合酶（5-LO）和环氧化酶（CO）的抑制剂，可抑制LPS诱导的TNFα和IL-1β释放，半数抑制浓度（IC50）为1微摩尔。在此剂量下，它还能抑制三种单克隆抗体诱导的两种细胞因子释放，抑制率>50%。己酮可可碱是一种具有磷酸二酯酶抑制活性的甲基黄嘌呤衍生物，选择性抑制LPS诱导的TNFα释放，IC50为100微摩尔。在存在100微摩尔己酮可可碱的情况下，单克隆抗体介导的TNFα和IL-1β释放受到的抑制小于30%。这些结果表明：（a）LPS诱导的细胞因子释放与生理相关刺激（涉及细胞表面受体交联）有共同步骤，且该途径对SK&F 86002的抑制敏感；（b）在抑制两种刺激诱导的TNFα和IL-1β释放方面，SK&F 86002比己酮可可碱更有效。
