Fiorucci S, Santucci L, Antonelli E, Distrutti E, Del Sero G, Morelli O, Romani L, Federici B, Del Soldato P, Morelli A
Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Università degli Studi di Perugia, Perugia, Italy.
Gastroenterology. 2000 Feb;118(2):404-21. doi: 10.1016/s0016-5085(00)70223-x.
BACKGROUND & AIMS: Concanavalin A (con A)-induced hepatitis is an immunomediated disease in which assembly of CD4(+) T cells and T helper (Th)1-like cytokines causes Fas-mediated liver cell death. Nitric oxide (NO) modulates Th1 response in vitro. NCX-4016 is an NO-aspirin derivative that spares the gastrointestinal tract and shares molecular targets with NO. The aim of this study was to investigate whether this NO-aspirin modulates Th1-like response induced by con A.
BALB/c mice were injected with 0.3 mg con A per mouse alone or in combination with NO-aspirin (18-100 mg/kg) or aspirin (10-55 mg/kg).
NO-aspirin, but not aspirin, caused a dose-dependent 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)-1beta, IL-12, IL-18, interferon (IFN)-gamma, and tumor necrosis factor alpha production without affecting cytokine messenger RNA expression. NO-aspirin prevented Fas, Fas ligand, and IL-2 receptor up-regulation on spleen lymphocytes and Fas ligand on hepatocytes and caused the S-nitrosylation/inhibition of IL-1beta-converting enzyme-like cysteine proteases (caspases) involved in the processing and maturation of IL-1beta and IL-18. IL-18 immunoneutralization prevented IFN-gamma release and protected from liver injury induced by con A. In contrast to a selective caspase 1 inhibitor, zVAD.FMK, a pancaspase inhibitor, prevented IFN-gamma release and protected the liver from injury.
Th1-like response induced by con A is mediated by IL-18 and requires activation of multiple caspases. NCX-4016 causes the S-nitrosylation/inhibition of caspases involved in cytokine production. Inhibition of Th1-like response is a new anti-inflammatory mechanism of action of NO-aspirin.
伴刀豆球蛋白A（Con A）诱导的肝炎是一种免疫介导性疾病，其中CD4(+) T细胞和Th1样细胞因子的聚集导致Fas介导的肝细胞死亡。一氧化氮（NO）在体外调节Th1反应。NCX - 4016是一种NO - 阿司匹林衍生物，对胃肠道有保护作用且与NO有共同的分子靶点。本研究旨在探讨这种NO - 阿司匹林是否能调节Con A诱导的Th1样反应。
给BALB / c小鼠单独注射每只0.3 mg Con A，或与NO - 阿司匹林（18 - 100 mg / kg）或阿司匹林（10 - 55 mg / kg）联合注射。
NO - 阿司匹林而非阿司匹林对Con A诱导的肝损伤具有剂量依赖性保护作用。在100 mg / kg剂量下，NO - 阿司匹林使白细胞介素（IL）-1β、IL - 12、IL - 18、干扰素（IFN）-γ和肿瘤坏死因子α的产生减少40% - 80%，而不影响细胞因子信使核糖核酸的表达。NO - 阿司匹林可防止脾脏淋巴细胞上Fas、Fas配体和IL - 2受体上调以及肝细胞上Fas配体上调，并导致参与IL - 1β和IL - 18加工和成熟的IL - 1β转化酶样半胱氨酸蛋白酶（胱天蛋白酶）的S - 亚硝基化/抑制。IL - 18免疫中和可防止IFN - γ释放并保护小鼠免受Con A诱导的肝损伤。与选择性胱天蛋白酶1抑制剂zVAD.FMK不同，一种泛胱天蛋白酶抑制剂可防止IFN - γ释放并保护肝脏免受损伤。
Con A诱导的Th1样反应由IL - 18介导，且需要多种胱天蛋白酶激活。NCX - 4016导致参与细胞因子产生的胱天蛋白酶的S - 亚硝基化/抑制。抑制Th1样反应是NO - 阿司匹林新的抗炎作用机制。
