Ligands for peroxisome proliferator-activated receptor γ (PPAR-γ), such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) have been implicated as a new class of anti-inflammatory compounds with possible clinical applications. Based on this concept, this investigation was designed to determine the effect of 15d-PGJ2-mediated activation of PPAR-γ ligand on neutrophil migration after an inflammatory stimulus and clarify the underlying molecular mechanisms using a mouse model of peritonitis. Our results demonstrated that 15d-PGJ2 administration decreases leukocyte rolling and adhesion to the inflammated mesenteric tissues by a mechanism dependent on NO. Specifically, pharmacological inhibitors of NO synthase remarkably abrogated the 15d-PGJ2-mediated suppression of neutrophil migration to the inflammatory site. Moreover, inducible NOS−/− mice were not susceptible to 15d-PGJ2-mediated suppression of neutrophil migration to the inflammatory sites when compared with their wild type. In addition, 15d-PGJ2-mediated suppression of neutrophil migration appeared to be independent of the production of cytokines and chemokines, since their production were not significantly affected in the carrageenan-injected peritoneal cavities. Finally, up-regulation of carrageenan-triggered ICAM-1 expression in the mesenteric microcirculation vessels was abrogated by pretreatment of wild-type mice with 15d-PGJ2, whereas 15d-PGJ2 inhibited F-actin rearrangement process in neutrophils. Taken together these findings demonstrated that 15d-PGJ2 suppresses inflammation-initiated neutrophil migration in a mechanism dependent on NO production in mesenteric tissues.
The 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) is an endogenous ligand of peroxisome proliferator-activated receptors ␥ (PPAR-␥) and is now recognized as a potent anti-inflammatory mediator. However, information regarding the influence of 15d-PGJ 2 on inflammatory pain is still unknown. In this study, we evaluated the effect of 15d-PGJ 2 upon inflammatory hypernociception and the mechanisms involved in this effect. We observed that intraplantar administration of 15d-PGJ 2 (30 -300 ng/paw) inhibits the mechanical hypernociception induced by both carrageenan (100 g/paw) and the directly acting hypernociceptive mediator, prostaglandin E 2 (PGE 2 ). Moreover, 15d-PGJ 2 [100 ng/temporomandibular joint (TMJ)] inhibits formalininduced TMJ hypernociception. On the other hand, the direct administration of 15d-PGJ 2 into the dorsal root ganglion was ineffective in blocking PGE 2 -induced hypernociception. In addition, the 15d-PGJ 2 antinociceptive effect was enhanced by the increase of macrophage population in paw tissue due to local injection of thioglycollate, suggesting the involvement of these cells on the 15d-PGJ 2 -antinociceptive effect. Moreover, the antinociceptive effect of 15d-PGJ 2 was also blocked by naloxone and by the PPAR-␥ antagonist 2-chloro-5-nitro-Nphenylbenzamide (GW9662), suggesting the involvement of peripheral opioids and PPAR-␥ receptor in the process. Similar to opioids, the 15d-PGJ 2 antinociceptive action depends on the nitric oxide/cGMP/protein kinase G (PKG)/K ATP ϩ channel pathway because it was prevented by the pretreatment with the inhibitors of nitric-oxide synthase (N G -monomethyl-L-arginine acetate), guanylate cyclase ]1H-(1,2,4)-oxadiazolo(4,2-␣)quinoxalin-1-one [, PKG [indolo[2,pyrrolo [3,4-c]carbazole aglycone (KT5823)], or with the ATP-sensitive potassium channel blocker glibenclamide. Taken together, these results demonstrate for the first time that 15d-PGJ 2 inhibits inflammatory hypernociception via PPAR-␥ activation. This effect seems to be dependent on endogenous opioids and local macrophages.
Periodontitis is a disease that leads to bone destruction and represents the main cause of tooth loss in adults. The development of aggressive periodontitis has been associated with increased inflammatory response that is induced by the presence of a subgingival biofilm containing Aggregatibacter actinomycetemcomitans. The flavonoid quercetin (1) is widespread in vegetables and fruits and exhibits many biological properties for possible medical and clinical applications such as its anti-inflamatory and antioxidant effects. Thus, in the present study, the properties of 1 have been evaluated in bone loss and inflammation using a mouse periodontitis model induced by A. actinomycetemcomitans infection. Subcutaneous treatment with 1 reduced A. actinomycetemcomitans-induced bone loss and IL-1β, TNF-α, IL-17, RANKL, and ICAM-1 production in the gingival tissue without affecting bacterial counts. These results demonstrated that quercetin exhibits protective effects in A. actinomycetemcomitans-induced periodontitis in mice by modulating cytokine and ICAM-1 production.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.