Milenković Marina, Arsenović-Ranin Nevena, Vucićević Dragana, Bufan Biljana, Jancić Ivan, Stojić-Vukanić Zorica
Department of Microbiology and Immunology, Faculty of Pharmacy, Vojvode Stepe, Belgrade, Serbia.
Arch Med Res. 2008 Oct;39(7):639-46. doi: 10.1016/j.arcmed.2008.07.003.
Fumaric acid esters (FAE) have been proven to be effective for the systemic treatment of psoriasis and multiple sclerosis, Th1 cell-mediated chronic inflammatory diseases, but their effect on autoimmune myocarditis has not yet been addressed. We investigated the effect of dimethyl fumarate (DMF) on myosin-induced experimental autoimmune myocarditis (EAM).
Dark Agouti (DA) rats immunized with porcine cardiac myosin were orally treated with 5 and 15 mg/kg body weight (bw) DMF either from days 0-10 (early treatment groups) or from days 10-21 (late treatment groups) after induction of EAM. All rats were sacrificed on day 21 after immunization and hearts were evaluated macroscopically and microscopically. Levels of TNF-alpha and IL-10 in serum and lymph node cells culture supernatants were detected by ELISA.
Both early and late treatment with 15 mg/kg body weight (bw) DMF markedly reduced the severity of myocarditis by comparing the incidence, heart weight/bw ratio, macroscopic and microscopic scores, and number of OX-6+ cells in the myocardium. Further, levels of tumor necrosis factor-alpha (TNF-alpha) in serum and culture supernatants of lymph node cells stimulated with ConA or myosin were significantly lower in DMF-treated EAM animals compared with vehicle-treated EAM rats. There was no significant difference in serum levels of interleukin-10 between DMF- and vehicle-treated EAM rats.
These results show for the first time that DMF ameliorates experimental autoimmune myocarditis and may be acted, at least in part, by interfering with the production of TNF-alpha.
富马酸酯（FAE）已被证明对银屑病和多发性硬化症等Th1细胞介导的慢性炎症性疾病的全身治疗有效，但其对自身免疫性心肌炎的影响尚未得到研究。我们研究了富马酸二甲酯（DMF）对肌球蛋白诱导的实验性自身免疫性心肌炎（EAM）的影响。
用猪心肌肌球蛋白免疫的暗褐鼠（DA大鼠），在EAM诱导后第0 - 10天（早期治疗组）或第10 - 21天（晚期治疗组），分别给予5和15 mg/kg体重（bw）的DMF口服治疗。所有大鼠在免疫后第21天处死，对心脏进行大体和显微镜评估。通过ELISA检测血清和淋巴结细胞培养上清液中TNF-α和IL-10的水平。
与溶剂处理的EAM大鼠相比，15 mg/kg体重（bw）的DMF早期和晚期治疗均通过比较心肌炎的发病率、心脏重量/体重比、大体和显微镜评分以及心肌中OX-6 +细胞数量，显著降低了心肌炎的严重程度。此外，与溶剂处理的EAM大鼠相比，用DMF治疗的EAM动物中，用ConA或肌球蛋白刺激的淋巴结细胞的血清和培养上清液中的肿瘤坏死因子-α（TNF-α）水平显著降低。DMF处理和溶剂处理的EAM大鼠之间血清白细胞介素-10水平无显著差异。
这些结果首次表明，DMF可改善实验性自身免疫性心肌炎，并且可能至少部分通过干扰TNF-α的产生起作用。
