Abstract
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.
Highlights
P2X7 receptor antagonists demonstrate antinociceptive and anti-inflammatory action and some of them are in clinical trials for treatment of chronic inflammatory diseases [1,2,3]
We found that the IL-8 release was blocked by an antagonist of P2X7 receptor, AZ11645373 (Fig. 1b)
A novel finding done in this work is that a P2X7 antagonist AZ11645373 inhibited expression of inflammatory molecules induced by chemically different classes of agonists including inflammatory cytokines, bacterial PAMPs, and endogenously generated DAMPs
Summary
P2X7 receptor antagonists demonstrate antinociceptive and anti-inflammatory action and some of them are in clinical trials for treatment of chronic inflammatory diseases [1,2,3]. It is generally accepted that the anti-inflammatory action of P2X7 receptor antagonists is mediated through the inhibition of P2X7 receptor-dependent activation of the NLRP-3 inflammasome [4,5,6]. Activation of P2X7 receptors by extracellular adenosine triphosphate induces efflux of potassium ions from cells resulting in activation of caspase, which processes IL-1β and IL-18 precursor proteins to the Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria
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