title: 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.
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.
authors.affiliation: 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.).
authors.forename: Pedro Miguel
authors.initials: PM
authors.lastname: Lacal
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Petrillo
authors.forename: Federica
authors.initials: F
authors.lastname: Ruffini
authors.forename: Alessia
authors.initials: A
authors.lastname: Muzi
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bianchini
authors.forename: Simona
authors.initials: S
authors.lastname: Ronchetti
authors.forename: Graziella
authors.initials: G
authors.lastname: Migliorati
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.forename: Grazia
authors.initials: G
authors.lastname: Graziani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002461:Cell Line, Transformed; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000819:agonists / Q000096:biosynthesis* / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007962:Leukocytes / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D048069:Tumor Necrosis Factors / Q000819:agonists / Q000096:biosynthesis* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D008024:Ligands; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1