ABSTRACT
Title
GITR gene deletion and GITR-Fc soluble protein administration inhibit multiple organ failure induced by zymosan
Authors
A. Venanzi1, M. Galuppo2, G. Nocentini1, E. Mazzon3, E. Esposito2, 3, L. Riccardi2, R. Di Paola2, S. Bruscoli1, C. Riccardi1 and S. Cuzzocrea2, 3.
1Dept. of Clinical and Experimental Medicine, Section of Pharmacology, University of Perugia, Italy.
2Dept. of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
3Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro Neurolesi "Bonino-Pulejo", Messina, Italy;
1Dept. of Clinical and Experimental Medicine, Section of Pharmacology, University of Perugia, Italy.
2Dept. of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
3Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro Neurolesi "Bonino-Pulejo", Messina, Italy;
Abstract
Multiple organs dysfunction syndrome (MODS) is a systemic inflammatory event that can result in organ damage, failure and high risk of mortality. 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-KO and two 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-WTgroup received GITR-Fc (6.25 mg/mouse; 3h 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-WTgroup with GITR-Fc (6.25 mg/mouse; 3h after saline injection) by mini-osmotic pump. A number of inflammatory parameters such as edema formation, histological damage, adhesion molecules expression, neutrophil infiltration, pro-inflammatory cytokines, nitrotyrosine, and iNOS production are significantly reduced in GITR-KO as compared to 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 WT mice, reduces inflammation, organ tissue damage and mortality. Results, while confirm the pro-inflammatory role of GITR extend our observations indicating that GITR plays a role in zymosan-induced inflammation and multiple organ dysfunction.
Mice were allocated into one GITR-KO and two 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-WTgroup received GITR-Fc (6.25 mg/mouse; 3h 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-WTgroup with GITR-Fc (6.25 mg/mouse; 3h after saline injection) by mini-osmotic pump. A number of inflammatory parameters such as edema formation, histological damage, adhesion molecules expression, neutrophil infiltration, pro-inflammatory cytokines, nitrotyrosine, and iNOS production are significantly reduced in GITR-KO as compared to 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 WT mice, reduces inflammation, organ tissue damage and mortality. Results, while confirm the pro-inflammatory role of GITR extend our observations indicating that GITR plays a role in zymosan-induced inflammation and multiple organ dysfunction.