Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody‐driven K/BxN serum–transfer arthritis

Abstract

Objective. Prostaglandins (PGs) are found in high levels in the synovial fluid of patients with rheumatoid arthritis, and nonsteroidal blockade of these bioactive lipids plays a role in patient care. The aim of this study was to explore the relative contribution of cyclooxygenase (COX) isoforms and PG species in the autoantibody-driven K/BxN serum-transfer arthritis.Methods. The prostanoid content of arthritic ankles was assessed in ankle homogenates, and the importance of this pathway was confirmed with pharmacologic blockade. The presence of COX isoforms was assessed by Western blotting and their functional contribution was compared using COX-1 ؊/؊ and COX-2 ؊/؊ mice as well as isoform-specific inhibitors. The relative importance of PGE 2 and PGI 2 (prostacyclin) was determined using mice deficient in microsomal PGE synthase 1 (mPGES-1) and in the receptors for PGI 2 .Results. High levels of PGE 2 and 6-keto-PGF 1␣ (a stable metabolite of PGI 2 ) were detected in arthritic joint tissues, correlating strongly with the intensity of synovitis. Pharmacologic inhibition of PG synthesis prevented arthritis and ameliorated active disease. While both COX isoforms were found in inflamed joint tissues, only COX-1 contributed substantially to clinical disease; COX-1 ؊/؊ mice were fully resistant to disease, whereas COX-2 ؊/؊ mice remained susceptible. These findings were confirmed by isoform-specific pharmacologic inhibition. Mice lacking mPGES-1 (and therefore PGE 2 ) developed arthritis normally, whereas mice incapable of responding to PGI 2 exhibited a significantly attenuated arthritis course, confirming a role of PGI 2 in this arthritis model. Conclusion. These findings challenge previous paradigms of distinct "housekeeping" versus inflammatory functions of the COX isoforms and highlight the potential pathogenic contribution of prostanoids synthesized via COX-1, in particular PGI 2 , to inflammatory arthritis.Prostaglandins (PGs) are lipid mediators that, in addition to their role in numerous physiologic activities, contribute to the pathogenesis of pathologic inflammation. They are generated by conversion of arachidonic acid by the cyclooxygenase (COX) enzymes to PGH 2 , which is further catalyzed by distinct synthases to 5 major bioactive prostaglandins (PGE 2 , PGI 2 , PGF 2␣ , Drs.

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A 2 -IIA

“…It was previously shown using the K/BxN serum transfer model of autoimmune arthritis that platelet COX-1 could generate large quantities of extracellular prostaglandin H 2 , which itself was metabolized transcellularly by the prostaclycin synthase expressed by fibroblast-like synoviocytes (53). The generation of prostacyclin by fibroblast-like synoviocytes amplifies inflammation, and, accordingly, the ablation of the gene coding for prostacyclin receptor reduces arthritis in vivo (54). The eicosanoid LTB 4 is also an important lipid mediator implicated in arthritis, and mice deficient in 5-lipoxygenase (the enzyme regulating its biosynthesis) and in BLT 1 (the high-affinity receptor for LTB 4 ) are resistant to arthritogenic K/BxN serum (26,55).…”

Platelets can enhance vascular permeability

“…37,50,54-61 Thromboxane A 2 and prostacyclin in particular are counterbalancing mediators, the former stimulating platelet aggregation and the latter inhibiting it. [58][59][60] Prostacyclin is present in mouse and human arthritic joints, 62,63 and we have demonstrated that platelets produce prostacyclin with synoviocytes using a transcellular mechanism during arthritis. 19,62,64 The balance between such mediators may thus impact platelet functions and guide the fate of the vasculature: its leakage or its preservation.…”

“…[58][59][60] Prostacyclin is present in mouse and human arthritic joints, 62,63 and we have demonstrated that platelets produce prostacyclin with synoviocytes using a transcellular mechanism during arthritis. 19,62,64 The balance between such mediators may thus impact platelet functions and guide (A) Serotonin concentrations were measured in whole blood from mast cell-deficient mice (Kit W-sh ), neutrophil-depleted mice, platelet-depleted mice, and their corresponding control mice using an ELISA serotonin kit. (B) Serotonin concentration was measured in platelet isolated from WT and Slc6a4 Ϫ/Ϫ mice.…”

Cytosolic Phospholipase A 2 α Contributes to Blood Pressure Increases and Endothelial Dysfunction Under Chronic NO Inhibition

“…The arachidonic acid (AA) cascade participates in the pathogenesis of acute and chronic inflammatory diseases, such as rheumatoid arthritis, 11,12 bronchial asthma, [13][14][15] and atherosclerotic diseases 16 -19 ; modulators of this cascade are commonly used in clinical practice. Inhibition of the downstream enzymes of AA cascade, including cyclooxygenase (COX) and lipoxygenase (LOX), is reported to modulate elevations in BP caused by chronic NO synthase (NOS) inhibition induced by treatment with N -nitro-L-arginine methyl ester (L-NAME).…”