NO-aspirin protects from T cell-mediated liver injury by inhibiting caspase-dependent processing of Th1-like cytokines

Background & Aims: Concanavalin A (con A)-induced hepatitis is an immunomed iated disease in which assembly of CD4+ T cells and T helper (Th)1-like cyt okines causes Fas-mediated liver cell death. Nitric oxide (NO) modulates Th 1 response in vitro. NCX-4016 is an NO-aspirin derivative that spares the g astrointestinal tract and shares molecular targets with NO. The aim of this study was to investigate whether this NO-aspirin modulates Th1-like respon se induced by con A. Methods: BALB/c mice were injected with 0.3 mg con A p er mouse alone or in combination with NO-aspirin (18-100 mg/kg) or aspirin (10-55 mg/kg). Results: NO-aspirin, but not aspirin, caused a dose-dependen t protection against liver damage induced by con A. At a dose of 100 mg/kg, NO-aspirin caused a 40%-80% reduction of interleukin (IL)-1 beta, IL-12, I L-18, interferon (IFN)-gamma, and tumor necrosis factor alpha production wi thout affecting cytokine messenger RNA expression. NO-aspirin prevented Pas , Pas ligand, and IL-2 receptor up-regulation on spleen lymphocytes and Fas ligand on hepatocytes and caused the S-nitrosylation/inhibition of IL-1 be ta-converting enzyme-like cysteine proteases (caspases) involved in the pro cessing and maturation of IL-1 beta and IL-18. IL-18 immunoneutralization p revented IFN-gamma release and protected from liver injury induced by con A . In contrast to a selective caspase 1 inhibitor, zVAD.FMK, a pancaspase in hibitor, prevented IFN-gamma release and protected the liver from injury. C onclusions: Th1-like response induced by con A is mediated by IL-18 and req uires activation of multiple caspases. NCX-4016 causes the S-nitrosylation/ inhibition of caspases involved in cytokine production. inhibition of Th1-l ike response is a new antiinflammatory mechanism of action of NO-aspirin.