Peroxisome Proliferator-Activated Receptor-γ Ligand, 15-Deoxy-Δ12,14-Prostaglandin J2, Reduces Neutrophil Migration via a Nitric Oxide Pathway

Abstract

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.

Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

“…Such association may limit binding of the leukocyte to the proadhesive ICAM-1. We have previously demonstrated that 15d-PGJ 2 was able to inhibit ICAM-1 (12). In addition, according to the current study, the use of 15d-PGJ 2 -NC at doses of 3 and 10 mg/kg increased the expression of the CD55 molecule in the gingival tissue.…”

“…Recently, our and other research groups have demonstrated the anti-inflammatory activity of exogenously administered 15d-PGJ 2 (12)(13)(14)(15)(16)(17)(18). However, it has been estimated that .50% of the 15d-PGJ 2 added exogenously to a biological system binds to albumin (11).…”

15d-PGJ2 modulates acute immune responses to Trypanosoma cruzi infection

“…This dose of 15d-PGJ 2 was chosen based on a previous study showing that it was effective as an anti-inflammatory agent (Napimoga et al 2008). The control group of infected animals (n = 8) was treated with DMSO only.…”

“…Furthermore, the release of TNF-α, IFN-γ, IL-4 and IL-10 by Con-A-stimulated splenocytes obtained from infected mice was significantly inhibited by treatment of the animals with salicylate or meloxicam (Michelin et al 2005). Interestingly, indomethacin binds and activates the peroxisome proliferator-activated receptor γ (PPARγ), a ligandactivated transcription factor known to play a pivotal role in adipogenesis (Lehmann et al 1997) in addition to the inflammatory process (Di Paola & Cuzzocrea 2007, Napimoga et al 2008.…”

“…As a consequence of the important roles, PPARs play in controlling metabolic homeostasis and inflammatory processes, they are often the therapeutic molecular targets for metabolic diseases such as diabetes (Chinetti et al 2000) and in the treatment of inflammatory disorders (Napimoga et al 2008, Hassumi et al 2009, Klotz et al 2009, Park et al 2009). In the present paper, we have investigated the effects of the 15d-PGJ 2 , an agonist of PPAR-γ, on disease outcome and immune function in T. cruzi-infected C57BL/6 mice.…”