Oskolkova Olga V, Godschachner Viktoria, Bochkov Valery N
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Humboldtstrasse 46/III, 8010, Graz, Austria.
Inflammation. 2017 Apr;40(2):530-536. doi: 10.1007/s10753-016-0499-8.
We have found that a well-characterized P2X7 receptor antagonist AZ11645373 blocked production of pro-inflammatory chemokine IL-8 in endothelial cells treated with OxPAPC. The effect was not due to toxicity of AZ11645373 as documented by cellular metabolic activity assay. The mechanism of inhibition by AZ11645373 was apparently independent of the P2X7 receptor because this receptor was not involved in induction of IL-8 under our experimental conditions. In support of this notion, two P2X7 agonists ATP and BzATP did not upregulate IL-8. On the other hand, a chemically different P2X7 receptor antagonist A740003 did not inhibit OxPAPC-induced production of IL-8. The inhibitory action of AZ11645373 was observed at the level of IL-8 protein and messenger RNA (mRNA) induction. Furthermore, AZ11645373 inhibited induction of mRNA encoding for COX-2 (PTGS2) suggesting that its anti-inflammatory potential is not limited to suppression of IL-8 production. In addition to inhibiting stimulation by OxPAPC, AZ11645373 suppressed induction of IL-8 by TNFα and LPS. To summarize, AZ11645373 inhibits in a P2X7-independent manner action of chemically different inflammatory agonists such as OxPLs, LPS, and TNFα. Thus, AZ11645373 may be especially effective for treatment of inflammatory disorders due to a beneficial combination of P2X7 receptor-dependent effects (inhibition of inflammasome activation, antinociceptive effects) with P2X7-independent general anti-inflammatory action described in this paper.
我们发现，一种特性明确的P2X7受体拮抗剂AZ11645373可阻断经氧化型磷脂酰胆碱（OxPAPC）处理的内皮细胞中促炎趋化因子白细胞介素-8（IL-8）的产生。细胞代谢活性测定表明，该效应并非由AZ11645373的毒性所致。AZ11645373的抑制机制显然独立于P2X7受体，因为在我们的实验条件下，该受体不参与IL-8的诱导。支持这一观点的是，两种P2X7激动剂三磷酸腺苷（ATP）和苯甲酰苯甲酰三磷酸腺苷（BzATP）并未上调IL-8。另一方面，一种化学结构不同的P2X7受体拮抗剂A740003并未抑制OxPAPC诱导的IL-8产生。在IL-8蛋白和信使核糖核酸（mRNA）诱导水平上观察到了AZ11645373的抑制作用。此外，AZ11645373抑制了编码环氧合酶-2（PTGS2）的mRNA的诱导，这表明其抗炎潜力不限于抑制IL-8的产生。除了抑制OxPAPC的刺激外，AZ11645373还抑制了肿瘤坏死因子α（TNFα）和脂多糖（LPS）诱导的IL-8产生。总之，AZ11645373以一种不依赖P2X7的方式抑制化学结构不同的炎性激动剂如氧化型磷脂（OxPLs）、LPS和TNFα的作用。因此，由于P2X7受体依赖性效应（抑制炎性小体激活、抗伤害感受作用）与本文所述的不依赖P2X7的一般抗炎作用的有益结合，AZ11645373可能对治疗炎性疾病特别有效。
