| Rheumatoid arthritis (RA) is a chronic disease characterized by cycles of inflammation and resolution. Previously, it was believed that the resolution of inflammation is simply dissipation of pro-inflammatory signals, although current research indicates that resolution is an active process. Acute inflammation follows defined phases of induction, inflammation and resolution, and resolution occurs by an active process that requires COX-2 activity. This study aims to address whether this paradigm extends to a recognized model of chronic inflammation. We demonstrated in murine collagen-induced arthritis that chronic inflammation follows the same sequential course. While there is the normal production of pro-inflammatory cytokines during inflammation and anti-inflammatory mediators such as 15-deoxyDelta12,14PGJ2 (15d-PGJ2) during resolution, interestingly there is sustained production of both COX-2 and the presumably pro-inflammatory PGE2 during both phases. Blocking COX-2 activity and therefore production of PGE 2 during the resolution phase perpetuated instead of attenuated inflammation. Repletion with PGE2 analogs restored homeostasis, and this function is mediated by the pro-resolving lipoxygenase metabolite, lipoxin A4 (LXA4), which is a potent stop signal. Thus, the study provided in vivo evidence for a natural, endogenous link between the cyclooxygenase-lipoxygenase pathways and showed that PGE2 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. |
