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Ligand, 15-Deoxy-
12,14-Prostaglandin J2, Reduces Neutrophil Migration via a Nitric Oxide Pathway1
,
* Laboratory of Molecular Biology, University of Uberaba, Minas Gerais, Brazil;
Department of Pharmacology
Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil;
Laboratory of Pharmacology, National Institute for Research in the Amazon, Manaus, Brazil; and
¶ Department of Immunology, The Forsyth Institute, Boston, MA 02115
Ligands for peroxisome proliferator-activated receptor 
(PPAR-), such as 15-deoxy-
12,14-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- 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Fundação de Amparo a Pesquisa do Estado de São Paulo Grant 05/60295-8, Fundaçao de Amparo à Pesquisa do Estado de Minas Gerais Grant 34/07, and National Institute of Dental and Craniofacial Research Grant DE 18310.
2 Address correspondence and reprint requests to Dr. Marcelo H. Napimoga, Laboratory of Molecular Biology, University of Uberaba, Avenue Nenê Sabino, 1801, Uberaba, Minas Gerais 38055-500, Brazil. E-mail address: marcelo.napimoga{at}uniube.br
3 Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor; 15d-PGJ2, 15-deoxy-12,14-prostaglandin J2; COX, cyclooxygenase; NOS, NO synthase; iNOS, inducible NOS; Cg, carrageenan; WT, wild type; DAPI, 4',6-diamidino-2-phenylindole; eNOS, endothelial NOS; nNOS, neuronal NOS; EC, endothelial cell; KC, keratinocyte chemokine.
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