title: The glucocorticoid-induced TNF receptor family-related protein (GITR) is critical to the development of acute pancreatitis in mice.
abstract: OBJECTIVE
  Pancreatitis represents a life-threatening inflammatory condition where leucocytes, cytokines and vascular endothelium contribute to the development of the inflammatory disease. The glucocorticoid-induced tumour necrosis factor (TNF) receptor family-related protein (GITR) is a costimulatory molecule for T lymphocytes, modulates innate and adaptive immune system and has been found to participate in a variety of immune responses and inflammatory processes. Our purpose was to verify whether inhibition of GITR triggering results in a better outcome in experimental pancreatitis.
  
  
  METHODS
  In male GITR knock-out (GITR(-/-)) and GITR(+/+) mice on Sv129 background, acute pancreatitis was induced after i.p. administration of cerulein. Other experimental groups of GITR(+/+) mice were also treated with different doses of Fc-GITR fusion protein (up to 6.25 µg·mouse⁻¹), given by implanted mini-osmotic pump. Clinical score and pro-inflammatory parameters were evaluated.
  
  
  RESULTS
  A less acute pancreatitis was found in GITR(-/-) mice than in GITR(+/+) mice, with marked differences in oedema, neutrophil infiltration, pancreatic dysfunction and injury. Co-treatment of GITR(+/+) mice with cerulein and Fc-GITR fusion protein (6.25 µg·mouse⁻¹) decreased the inflammatory response and tissue injury, compared with treatment with cerulein alone. Inhibition of GITR triggering was found to modulate activation of nuclear factor κB as well as the production of TNF-α, interleukin-1β, inducible nitric oxide synthase, nitrotyrosine, poly-ADP-ribose, intercellular adhesion molecule-1 and P-selectin.
  
  
  CONCLUSIONS
  The GITR-GITR ligand system is crucial to the development of acute pancreatitis in mice. Our results also suggest that the Fc-GITR fusion protein could be useful in the treatment of acute pancreatitis.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Galuppo
authors.forename: G
authors.initials: G
authors.lastname: Nocentini
authors.forename: E
authors.initials: E
authors.lastname: Mazzon
authors.forename: S
authors.initials: S
authors.lastname: Ronchetti
authors.forename: E
authors.initials: E
authors.lastname: Esposito
authors.forename: L
authors.initials: L
authors.lastname: Riccardi
authors.forename: P
authors.initials: P
authors.lastname: Sportoletti
authors.forename: R
authors.initials: R
authors.lastname: Di Paola
authors.forename: S
authors.initials: S
authors.lastname: Bruscoli
authors.forename: C
authors.initials: C
authors.lastname: Riccardi
authors.forename: S
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D017209:Apoptosis; D002108:Ceruletide / Q000633:toxicity; D004487:Edema / Q000209:etiology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D020556:Neutrophil Infiltration; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010195:Pancreatitis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D013601:T-Lymphocytes / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D008024:Ligands; C000606205:Nfkbia protein, mouse; D019007:P-Selectin; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C498144:Rela protein, mouse; C106544:Tnfrsf18 protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D002108:Ceruletide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases