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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/H1056    most recent 00266.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Véliz, L. P. Articles by Boric, M. P. PubMed PubMed Citation Articles by Véliz, L. P. Articles by Boric, M. P.

Functional role of gap junctions in cytokine-induced leukocyte adhesion to endothelium in vivo

¹Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, and ²Núcleo Milenio Inmunología e Inmunoterapia, Santiago, Chile; and ³Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia

Submitted 12 March 2008 ; accepted in final form 27 June 2008

To assess the hypothesis that gap junctions (GJs) participate on leukocyte-endothelium interactions in the inflammatory response, we compared leukocyte adhesion and transmigration elicited by cytokine stimulation in the presence or absence of GJ blockers in the hamster cheek pouch and also in the cremaster muscle of wild-type (WT) and endothelium-specific connexin 43 (Cx43) null mice (Cx43e^–/–). In the cheek pouch, topical tumor necrosis factor- (TNF-; 150 ng/ml, 15 min) caused a sustained increment in the number of leukocytes adhered to venular endothelium (LAV) and located at perivenular regions (LPV). Superfusion with the GJ blockers 18--glycyrrhetinic acid (AGA; 75 µM) or 18-β-glycyrrhetinic acid (50 µM) abolished the TNF--induced increase in LAV and LPV; carbenoxolone (75 µM) or oleamide (100 µM) reduced LAV by 50 and 75%, respectively, and LPV to a lesser extent. None of these GJ blockers modified venular diameter, blood flow, or leukocyte rolling. In contrast, glycyrrhizin (75 µM), a non-GJ blocker analog of AGA, was devoid of effect. Interestingly, when AGA was removed 90 min after TNF- stimulation, LAV started to rise at a similar rate as in control. Conversely, application of AGA 90 min after TNF- reduced the number of previously adhered cells. In WT mice, intrascrotal injection of TNF- (0.5 µg/0.3 ml) increased LAV (fourfold) and LPV (threefold) compared with saline-injected controls. In contrast to the observations in WT animals, TNF- stimulation did not increase LAV or LPV in Cx43e^–/– mice. These results demonstrate an important role for GJ communication in leukocyte adhesion and transmigration during acute inflammation in vivo and further suggest that endothelial Cx43 is key in these processes.

inflammation; tumor necrosis factor-; endothelial-connexin 43 knock-out mice; gap junction blockers