He Quanren, Kim Jiyoung, Sharma Raghubir P
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
Toxicology. 2005 Feb 1;207(1):137-47. doi: 10.1016/j.tox.2004.09.013.
Fumonisin B1 (FB1) is a toxic and carcinogenic mycotoxin produced by Fusarium verticillioides found on corn worldwide. The biological effects of FB1 are attributed to sphingolipid metabolism disruption as a result of ceramide synthase inhibition. Tumor necrosis factor alpha (TNFalpha) is an important modulator of FB1 hepatotoxicity. Kupffer cells are major source of cytokine production in liver. In the present study we investigated the effects of Kupffer cell depletion by gadolinium on FB1 hepatotoxicity in female BALB/c mice. Mice were given saline or 50 mg/kg of gadolinium chloride once via the tail vein; 16 h later they were treated with subcutaneous injections of vehicle or 2.25 mg/kg/day FB1 in saline for three successive days. Gadolinium significantly attenuated FB1-induced increases in the activities of circulating alanine aminotransferase and aspartate aminotransferase and reduced the FB1-induced hepatocyte apoptosis and free sphinganine accumulation in liver. Both gadolinium and FB1 treatments individually increased the expression of selected cell signal factors; e.g., TNFalpha, TNF receptor 1, TNF-related apoptosis-inducing ligand, lymphotoxin beta, interferon gamma, and transforming growth factor beta1; gadolinium chloride did not alter FB1-induced expression of the above genes. Results indicated that Kupffer cells play a role in FB1 hepatotoxicity. Decreased FB1-induced sphinganine accumulation and increased protective TNFalpha signaling by gadolinium chloride may in part account for its ameliorating effect on FB1 liver damage.
伏马菌素B1(FB1)是一种由轮枝镰孢菌产生的有毒致癌霉菌毒素,在全球范围内的玉米上均有发现。FB1的生物学效应归因于神经酰胺合酶抑制导致的鞘脂代谢紊乱。肿瘤坏死因子α(TNFα)是FB1肝毒性的重要调节因子。库普弗细胞是肝脏中细胞因子产生的主要来源。在本研究中,我们研究了用钆使库普弗细胞耗竭对雌性BALB/c小鼠FB1肝毒性的影响。小鼠通过尾静脉一次性给予生理盐水或50 mg/kg氯化钆;16小时后,它们连续三天皮下注射溶媒或2.25 mg/kg/天的FB1生理盐水溶液。钆显著减轻了FB1诱导的循环丙氨酸转氨酶和天冬氨酸转氨酶活性升高,并减少了FB1诱导的肝细胞凋亡和肝脏中游离鞘氨醇的积累。钆和FB1单独处理均增加了所选细胞信号因子的表达;例如,TNFα、TNF受体1、TNF相关凋亡诱导配体、淋巴毒素β、干扰素γ和转化生长因子β1;氯化钆并未改变FB1诱导的上述基因的表达。结果表明,库普弗细胞在FB1肝毒性中起作用。氯化钆减少FB1诱导的鞘氨醇积累并增加保护性TNFα信号传导,这可能部分解释了其对FB1肝损伤的改善作用。