Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production.
Acute inflammation follows defined phases of induction, inflammation and resolution, and resolution occurs by an active process that requires cyclooxygenase-2 (COX-2) activity. This study aims to address whether this paradigm extends to recognized model of chronic inflammation. We demonstrated that murine collagen-induced arthritis follows a similar sequential course. Interestingly, COX-2 and its metabolite, the presumably proinflammatory PGE(2), are present in the joints during resolution, and blocking COX-2 activity and PGE(2) production within this period perpetuated, instead of attenuated, inflammation. Repletion with PGE(2) analogs restored homeostasis, and this function is mediated by the proresolving lipoxygenase metabolite, lipoxin A(4), a potent stop signal. Thus, the study provided in vivo evidence for a natural, endogenous link between the cyclooxygenase-lipoxygenase pathways and showed that PGE(2) serves as a feedback inhibitor essential for limiting chronic inflammation in autoimmune arthritis. These findings may explain the enigma regarding why COX-2 inhibitors are palliative rather than curative in humans, because blocking resolution may mitigate the benefit of preventing induction.
Chan
Marion Man-Ying
MM
Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA 19140, USA. marion.chan@temple.edu
Moore
Andrea Rossi
AR
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology*; D044045:Lipoxins / Q000096:biosynthesis* / Q000502:physiology; D008297:Male; D051379:Mice; D009578:Nitrobenzenes / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D018836:Inflammation Mediators; D044045:Lipoxins; D009578:Nitrobenzenes; D013449:Sulfonamides; C040527:lipoxin A4; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D015232:Dinoprostone