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: Maria Galuppo, Giuseppe Nocentini, Emanuela Mazzon, Simona Ronchetti, Emanuela Esposito, Luisa Riccardi, Rosanna Di Paola, Stefano Bruscoli, Carlo Riccardi, Salvatore Cuzzocrea
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 36 Issue 3 Pg. 263-71 (Sep 2011) ISSN: 1540-0514 [Electronic] United States
• PMID: 21654556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• Glucocorticoid-Induced TNFR-Related Protein
• Interleukin-1beta
• Interleukin-6
• Nitrates
• Nitrites
• Recombinant Fusion Proteins
• Tnfrsf18 protein, mouse
• Tumor Necrosis Factor-alpha
• Zymosan
• Peroxidase

Topics

• Animals
• Cell Adhesion Molecules
• Gene Deletion
• Glucocorticoid-Induced TNFR-Related Protein (genetics, metabolism)
• Immunohistochemistry
• Interleukin-1beta (metabolism)
• Interleukin-6 (metabolism)
• Male
• Mice
• Mice, Knockout
• Multiple Organ Failure (chemically induced, genetics, metabolism, prevention & control)
• Nitrates (metabolism)
• Nitrites (metabolism)
• Peroxidase (metabolism)
• Recombinant Fusion Proteins (genetics, therapeutic use)
• Tumor Necrosis Factor-alpha (metabolism)
• Zymosan (toxicity)