The cardinal role of the phospholipase A2/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E2 (PCPP) axis in inflammostasis

Abstract

The process of inflammation is regulated in part by bioactive lipids of which prostaglandins/eicosanoids form an important class. We provide evidence that the phospholipase A(2)/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E(2) (PCPP) axis is positioned at the core of a natural regulatory circuit controlling the initiation, magnitude, duration, and resolution of the inflammatory response. During the inflammatory phase, proinflammatory cytokine, chemokine and matrix destructive metalloprotease expression levels are moderated by the PCPP axis through the modulation of signaling pathways that control proinflammatory gene expression at transcriptional, post-transcriptional, and translational levels. The PCPP axis also contributes to the activation of lipid mediator class switching; this highly coordinated process results in the biosynthesis of lipoxins and resolvins that promote inflammatory resolution through a variety of cellular and molecular mechanisms. The PCPP axis activity is autoregulated by way of a positive feedback circuit involving PGE(2)-mediated, p38 MAPK-dependent stabilization of COX-2 mRNA and COX-2 catalytic potentiation via its limited proteolytic cleavage (e.g., Ca(2+)-activated calpains). In conclusion, through its fine temporal modulation of multiple signaling cassettes via EP1-EP4 GPCRs, PGE(2) influences the onset, course, magnitude, and duration of the inflammatory response and functions as a key feedback regulator of the cellular and molecular processes controlling inflammation.

Leukotriene B4 BLT Receptor Signaling Regulates the Level and Stability of Cyclooxygenase-2 (COX-2) mRNA through Restricted Activation of Ras/Raf/ERK/p42 AUF1 Pathway

“…The congruity of our results using different experimental approaches and cell types strengthens the validity of our observations. Nevertheless, we used an overexpression protocol, and although pan-AUF1 (predominantly nuclear) and TTP (cytoplasmic) were modestly expressed in our cell types, HuR is abundantly expressed and partitions between the nuclear and cytoplasmic compartments (50,51). The results may be subject to interpretation as it is FIGURE 6.…”

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2α and Eicosanoid Production in Monocytes and Macrophages

“…LMW HA-induced PGE 2 Production Is cPLA 2 ␣-dependent-PGE 2 is one of the specific downstream eicosanoids, produced by cyclooxygenases 1 (COX1 or PTGS1) and 2 (COX2 or PTGS2), from the release of AA from membrane phospholipids (60). To evaluate if PGE 2 production could be stimulated by HA and to address the question of cPLA 2 ␣ dependence, we treated different cell types with HA (100 g/ml) in the presence or absence of cPLA 2 ␣ inhibitor (2 M).…”

The Neuroinflammation in the Physiopathology of Amyotrophic Lateral Sclerosis

“…COX-2 is a pro-inflammatory enzyme that converts arachidonic acid into prostanoids such as PGE 2 , a potent inflammatory mediator (reviewed in [60]). In the anterior horn region of the spinal cord of SOD1 G93A mice, at both the early and end stage of the disease, COX-2 immunoreactivity is elevated in astrocytes [61].…”

“…COX-2 appears as an appealing therapeutic target for ALS as it promotes both pro-inflammatory events and astrocytic glutamate release [60,67]. Celecoxib, a COX-2 inhibitor, fed to SOD1 G93A mice from asymptomatic to end-stage results in a delayed onset and an increased lifespan of approximately 25%.…”