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      Glucocorticoid-induced tumor necrosis factor receptor family-related ligand triggering upregulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 and promotes leukocyte adhesion.

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          Abstract

          The interaction of glucocorticoid-induced tumor necrosis factor receptor-family related (GITR) protein with its ligand (GITRL) modulates different functions, including immune/inflammatory response. These effects are consequent to intracellular signals activated by both GITR and GITRL. Previous results have suggested that lack of GITR expression in GITR(-/-) mice decreases the number of leukocytes within inflamed tissues. We performed experiments to analyze whether the GITRL/GITR system modulates leukocyte adhesion and extravasation. For that purpose, we first evaluated the capability of murine splenocytes to adhere to endothelial cells (EC). Our results indicated that adhesion of GITR(-/-) splenocytes to EC was reduced as compared with wild-type cells, suggesting that GITR plays a role in adhesion and that this effect may be due to GITRL-GITR interaction. Moreover, adhesion was increased when EC were pretreated with an agonist GITR-Fc fusion protein, thus indicating that triggering of GITRL plays a role in adhesion by EC regulation. In a human in vitro model, the adhesion to human EC of HL-60 cells differentiated toward the monocytic lineage was increased by EC pretreatment with agonist GITR-Fc. Conversely, antagonistic anti-GITR and anti-GITRL Ab decreased adhesion, thus further indicating that GITRL triggering increases the EC capability to support leukocyte adhesion. EC treatment with GITR-Fc favored extravasation, as demonstrated by a transmigration assay. Notably, GITRL triggering increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and anti-ICAM-1 and anti-VCAM-1 Abs reversed GITR-Fc effects. Our study demonstrates that GITRL triggering in EC increases leukocyte adhesion and transmigration, suggesting new anti-inflammatory therapeutic approaches based on inhibition of GITRL-GITR interaction.

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          Author and article information

          Journal
          J Pharmacol Exp Ther
          The Journal of pharmacology and experimental therapeutics
          American Society for Pharmacology & Experimental Therapeutics (ASPET)
          1521-0103
          0022-3565
          Oct 2013
          : 347
          : 1
          Affiliations
          [1 ] Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata-IRCCS," Rome, Italy (P.M.L., F.R.); Department of Medicine, University of Perugia, Perugia, Italy (M.G.P., R.B., S.R., G.M., C.R., G.N.); and Department of System Medicine, University of Rome "Tor Vergata," Rome, Italy (A.M., G.G.).
          Article
          jpet.113.207605
          10.1124/jpet.113.207605
          23892569
          584d99ff-164c-4dd9-9671-ca6bc9834215
          History

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