Napimoga Marcelo H, Vieira Silvio M, Dal-Secco Daniela, Freitas Andressa, Souto Fabrício O, Mestriner Fabiola L, Alves-Filho José C, Grespan Renata, Kawai Toshihisa, Ferreira Sérgio H, Cunha Fernando Q
Laboratory of Molecular Biology, University of Uberaba, Minas Gerais, Brazil.
J Immunol. 2008 Jan 1;180(1):609-17. doi: 10.4049/jimmunol.180.1.609.
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.
过氧化物酶体增殖物激活受体γ（PPAR-γ）的配体，如15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2），已被认为是一类具有潜在临床应用价值的新型抗炎化合物。基于这一概念，本研究旨在确定15d-PGJ2介导的PPAR-γ配体激活对炎症刺激后中性粒细胞迁移的影响，并使用腹膜炎小鼠模型阐明其潜在的分子机制。我们的结果表明，给予15d-PGJ2可通过一种依赖于一氧化氮（NO）的机制减少白细胞在炎症肠系膜组织上的滚动和黏附。具体而言，NO合酶的药理学抑制剂显著消除了15d-PGJ2介导的对中性粒细胞向炎症部位迁移的抑制作用。此外，与野生型小鼠相比，诱导型一氧化氮合酶基因敲除（iNOS-/-）小鼠对15d-PGJ2介导的中性粒细胞向炎症部位迁移的抑制作用不敏感。此外，15d-PGJ2介导的对中性粒细胞迁移的抑制作用似乎与细胞因子和趋化因子的产生无关，因为在注射角叉菜胶的腹腔中它们的产生没有受到显著影响。最后，用15d-PGJ2预处理野生型小鼠可消除角叉菜胶触发的肠系膜微循环血管中细胞间黏附分子-1（ICAM-1）表达的上调，而15d-PGJ2抑制中性粒细胞中的F-肌动蛋白重排过程。综上所述，这些发现表明15d-PGJ2通过一种依赖于肠系膜组织中NO产生的机制抑制炎症引发的中性粒细胞迁移。
