Peroxisome proliferator-activated receptor-gamma ligand, 15-deoxy-Delta12,14-prostaglandin J2, reduces neutrophil migration via a nitric oxide pathway.
Ligands for peroxisome proliferator-activated receptor gamma (PPAR-gamma), such as 15-deoxy-Delta12,14-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-gamma 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 inflamed 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.
Napimoga
Marcelo H
MH
Laboratory of Molecular Biology, University of Uberaba, Minas Gerais, Brazil. marcelo.napimoga@uniube.br
Vieira
Silvio M
SM
Dal-Secco
Daniela
D
Freitas
Andressa
A
Souto
Fabrício O
FO
Mestriner
Fabiola L
FL
Alves-Filho
José C
JC
Grespan
Renata
R
Kawai
Toshihisa
T
Ferreira
Sérgio H
SH
Cunha
Fernando Q
FQ
D000199:Actins / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000378:metabolism; D002351:Carrageenan / Q000494:pharmacology; D002448:Cell Adhesion; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036904:Leukocyte Rolling; D008024:Ligands; D008297:Male; D008643:Mesentery / Q000098:blood supply; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000199:Actins; D008024:Ligands; D047495:PPAR gamma; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D002351:Carrageenan; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2