title: GITR gene deletion and GITR-FC soluble protein administration inhibit multiple organ failure induced by zymosan.
abstract: Multiple organ dysfunction syndrome (MODS) is a systemic inflammatory event that can result in organ damage, failure, and high risk of mortality. The aim of this study was to evaluate the possible role of glucocorticoid-induced TNFR-related (GITR) on zymosan-induced MODS. Mice were allocated into one GITR knockout (GITR-KO) and two GITR wild-type (GITR-WT) experimental groups. All the animals were treated with zymosan (500 mg/kg, suspended in saline solution, i.p.), and animals of one GITR-WT group received GITR-Fc (6.25 μg/mouse; 3 h after zymosan injection) by mini-osmotic pump. Moreover, three control groups were performed (one GITR-KO and two GITR-WT experimental groups), administering saline instead of zymosan and treating one of the GITR-WT group with GITR-Fc (6.25 μg/mouse; 3 h after saline injection) by mini-osmotic pump. A number of inflammatory parameters such as edema formation, histological damage, adhesion molecules expression, neutrophil infiltration, proinflammatory cytokines, nitrotyrosine, and iNOS production are significantly reduced in GITR-KO as compared with GITR-WT mice as well as in GITR-WT mice treated with GITR-Fc. We here show that GITR plays a role in the modulation of experimental MODS. In particular, we show that genetic inhibition of GITR expression, in GITR-KO mice, or administration of soluble GITR-Fc receptor in GITR-WT mice, reduces inflammation, organ tissue damage, and mortality. Results, while confirming the proinflammatory role of GITR, extend our observations indicating that GITR plays a role in zymosan-induced inflammation and MODS.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Galuppo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Simona
authors.initials: S
authors.lastname: Ronchetti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Luisa
authors.initials: L
authors.lastname: Riccardi
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules; D017353:Gene Deletion; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015054:Zymosan / Q000633:toxicity*
chemical_list: D015815:Cell Adhesion Molecules; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D009566:Nitrates; D009573:Nitrites; D011993:Recombinant Fusion Proteins; C106544:Tnfrsf18 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D009195:Peroxidase