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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.
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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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  D. Dal-Secco, T. M. Cunha, A. Freitas, J. C. Alves-Filho, F. O. Souto, S. Y. Fukada, R. Grespan, N. M. N. Alencar, A. F. Neto, M. A. Rossi, et al. Hydrogen Sulfide Augments Neutrophil Migration through Enhancement of Adhesion Molecule Expression and Prevention of CXCR2 Internalization: Role of ATP-Sensitive Potassium Channels J. Immunol., September 15, 2008; 181(6): 4287 - 4298. [Abstract] [Full Text] [PDF]
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