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

Abstract

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. 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. 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. 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.