The glucocorticoid-induced TNF receptor family-related protein (GITR) is critical to the development of acute pancreatitis in mice

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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 mu g center dot mouse-1), given by implanted mini-osmotic pump. Clinical score and pro-inflammatory parameters were evaluated. KEY 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 mu g center dot 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 kappa B as well as the production of TNF-alpha, interleukin-1 beta, inducible nitric oxide synthase, nitrotyrosine, poly-ADP-ribose, intercellular adhesion molecule-1 and P-selectin. CONCLUSIONS AND IMPLICATIONS 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.