Cyclooxygenase (COX) has two isoforms. Generally, COX 1 is constitutively expressed in most tissues, where it maintains physiological processes; inducible COX 2 is considered a pro-inflammatory enzyme and a chief target for the treatment of inflammatory diseases. Here we present evidence that COX 2 may have anti-inflammatory properties. In carrageenin-induced pleurisy in rats, the predominant cells at 2 hours are polymorphonuclear leucocytes, whereas mononuclear cells dominate from 24 hours until resolution at 48 hours. In this model, COX 2 protein expression peaked initially at 2 hours, associated with maximal prostaglandin E2 synthesis. However, at 48 hours there was a second increase in COX 2 expression, 350% greater than that at 2 hours. Paradoxically, this coincided with inflammatory resolution and was associated with minimal prostaglandin E2 synthesis. In contrast, levels of prostaglandin D2, and 15deoxy delta(12-14)prostaglandin J2 were high at 2 hours, decreased as inflammation increased, but were increased again at 48 hours. The selective COX 2 inhibitor NS-398 and the dual COX 1/COX 2 inhibitor indomethacin inhibited inflammation at 2 hours but significantly exacerbated inflammation at 48 hours. This exacerbation was associated with reduced exudate prostaglandin D2 and 15deoxy delta(12-14)prostaglandin J2 concentrations, and was reversed by replacement of these prostaglandins. Thus, COX 2 may be pro-inflammatory during the early phase of a carrageenin-induced pleurisy, dominated by polymorphonuclear leucocytes, but may aid resolution at the later, mononuclear cell-dominated phase by generating an alternative set of anti-inflammatory prostaglandins.
Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-kappaB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-kappaB activation in leukocytes recruited during the onset of inflammation is associated with pro-inflammatory gene expression, whereas such activation during the resolution of inflammation is associated with the expression of anti-inflammatory genes and the induction of apoptosis. Inhibition of NF-kappaB during the resolution of inflammation protracts the inflammatory response and prevents apoptosis. This suggests that NF-kappaB has an anti-inflammatory role in vivo involving the regulation of inflammatory resolution.
Neutralizing injurious stimuli, proinflammatory mediator catabolism, and polymorphonuclear leukocyte (PMN) clearance are determinants of inflammatory resolution. To this, we recently added innate-type lymphocyte repopulation as being central for restoring postinflammation tissue homeostasis with a role in controlling innate immune–mediated responses to secondary infection. However, although macrophages dominate resolution, their phenotype and role in restoring tissue physiology once inflammation abates are unknown. Therefore, we isolated macrophages from the resolving phase of acute inflammation and found that compared with classically activated proinflammatory M1 cells, resolution-phase macrophages (rMs) possess weaker bactericidal properties and express an alternatively activated phenotype but with elevated markers of M1 cells including inducible cyclooxygenase (COX 2) and nitric oxide synthase (iNOS). This phenotype is controlled by cAMP, which, when inhibited, transforms rM to M1 cells. Conversely, elevating cAMP in M1 cells transforms them to rMs, with implications for cAMP in the resolution of systemic inflammation. It transpires that although rMs are dispensable for clearing PMNs during self-limiting inflammation, they are essential for signaling postresolution lymphocyte repopulation via COX 2 lipids. Thus, rM macrophages are neither classically nor alternatively activated but a hybrid of both, with a role in mediating postresolution innate-lymphocyte repopulation and restoring tissue homeostasis.
Aspirin is a unique nonsteroidal anti-inflammatory drug; at high doses (aspirinhigh, 1g), it is anti-inflammatory stemming from the inhibition of cyclooxygenase and proinflammatory signaling pathways including NF-κB, but is cardioprotective at lower doses (aspirinlow, 75 mg). The latter arises from the inhibition of thromboxane (Tx) B2, a prothrombotic eicosanoid also implicated in polymorphonuclear leukocyte trafficking. As a result, aspirinlow is widely used as a primary and secondary preventative against vascular disease. Despite this and its ability to synthesize proresolution 15-epi-lipoxin A4 it is not known whether aspirinlow is anti-inflammatory in humans. To address this, we generated skin blisters by topically applying cantharidin on the forearm of healthy male volunteers, causing an acute inflammatory response including dermal edema formation and leukocyte trafficking. Although not affecting blister fluid volume, aspirinlow (75 mg, oral, once daily/10 days) reduced polymorphonuclear leukocyte and macrophage accumulation independent of NF-κB-regulated gene expression and inhibition of conventional prostanoids. However, aspirinlow triggered 15-epi-lipoxin A4 synthesis and up-regulated its receptor (FPRL1, ALX). From complimentary in vitro experiments, we propose that 15-epi-lipoxin A4 exerts its protective effects by triggering antiadhesive NO, thereby dampening leukocyte/endothelial cell interaction and subsequent extravascular leukocyte migration. Since similar findings were obtained from murine zymosan-induced peritonitis, we suggest that aspirinlow possesses the ability to inhibit mammalian innate immune-mediated responses. This highlights 15-epi-lipoxin A4 as a novel anti-inflammatory working through a defined receptor and suggests that mimicking its mode of action represents a new approach to treating inflammation-driven diseases.
Hematopoietic prostaglandin D2 synthase (hPGD2S) metabolizes cyclooxygenase (COX)-derived PGH 2 to PGD2 and 15-deoxy⌬ 12-14 PGJ2 (15d-PGJ2). Unlike COX, the role of hPGD2S in host defense is ambiguous. PGD 2 can be either pro-or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ 2 and its relevance to pathophysiology remain controversial. Herein, studies on hPGD 2S KO mice reveal that 15d-PGJ2 is synthesized in a self-resolving peritonitis, detected by using liquid chromatography-tandem MS. Together with PGD 2 working on its DP1 receptor, 15d-PGJ 2 controls the balance of pro-vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD 2S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD 2S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/ chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ 2 is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy.antiinflammatory ͉ cyclooxygnease ͉ drug development ͉ eicosanoids ͉ innate immunity C yclooxygenase (COX) metabolizes phospholipase A 2 -derived arachidonic acid to prostaglandin (PG)H 2 , which is further metabolized by a series of downsteam synthases to the prostanoids. Indeed, the expression of the particular downstream enzyme and its coupling either to constitutively expressed COX1 or to inducible COX2 will determine the profile and levels of arachidonic metabolites released by cells. Thus, targeting COX will diminish most if not all prostanoids, which, in the case of new-generation COX2 inhibitors, resulted in prostacyclin abatement, enhanced risk of cardiovascular side effects, and the eventual withdrawal of selective COX2 inhibitors from clinical usage. In this event, attention has now shifted to understanding the role of COX downstream synthases in inflammation and the cardiovascular system in the hope of adding more selectivity with fewer side effects.In an attempt to understand the role of COX-related downstream synthase in host defense, we found that the COX2/ hematopoietic PGD 2 synthase pathway resolves both acute innate (1, 2) and adaptive immune responses (3). Hematopoietic PGD 2 synthase (hPGD 2 S) metabolizes COX-derived PGH 2 to PGD 2 (4), which may activate two G protein-coupled receptors, DP1 and DP2. DP1 regulates dendritic cell function (5), and DP2 promotes allergic inflammation (6-8). Although controversial, it is believed that PGD 2 is initially converted to PGJ 2 and 15-deoxy-PGD 2 (15d-PG...
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