Canault M, Peiretti F, Poggi M, Mueller C, Kopp F, Bonardo B, Bastelica D, Nicolay A, Alessi M-C, Nalbone G
Inserm, U626, Marseille, F-13385, France.
J Pathol. 2008 Apr;214(5):574-83. doi: 10.1002/path.2305.
TNFalpha (TNF) critically regulates inflammation-driven atherosclerosis. Because the transmembrane (tmTNF) and soluble (sTNF) forms of TNF possess distinct immuno-modulatory properties, we hypothesized that they might differentially regulate atherosclerosis progression. Three groups of male ApoE(-/-) mice were studied: one expressing wild-type TNF (WT-TNF); one expressing exclusively a mutated non-cleavable form of TNF (KI-TNF); and one deficient in TNF (KO-TNF). Mice aged 5 weeks were fed the high-fat diet for 5 (T5) and 15 weeks (T15) or a standard chow diet for 15 weeks. At T5, in mice fed the high-fat diet, no significant differences in lesion area were observed among the three groups, either in valves or in aortas. At T15, lesion areas in valves were significantly lower in KO-TNF mice compared with those in WT-TNF mice, whereas in KI-TNF mice, they were intermediate between KO- and WT-TNF mice but not significantly different from these two groups. In aortas, lesions in KI-TNF were comparable to those of KO-TNF, both being significantly lower than those in WT-TNF. Theses differences were not linked to circulating lipids, or to macrophage, actin, and collagen contents of lesions. At T15, in mice fed the chow diet, lesion areas in valves and the aortic arch were not significantly different between the three groups. Levels of IL-6, IFNgamma, IL-10, and Foxp3 mRNAs in spleens and production of IL-6, IL-10, MCP-1, RANTES, and TNFR-2 by peritoneal macrophages at T15 of the high-fat diet showed a decrease in pro-inflammatory status, more marked in KO-TNF than in KI-TNF mice. Apoptosis was reduced only in KO-TNF mice. In conclusion, these data show that TNF effects on atherosclerosis development are detectable at stages succeeding fatty streaks and that wild-type TNF is superior to tmTNF alone in promoting atherosclerosis. TNF-dependent progression of atherosclerosis is probably linked to the differential production of pro-inflammatory mediators whether tmTNF is preponderant or essentially cleaved.
肿瘤坏死因子α（TNF）对炎症驱动的动脉粥样硬化起着关键的调节作用。由于TNF的跨膜形式（tmTNF）和可溶性形式（sTNF）具有不同的免疫调节特性，我们推测它们可能对动脉粥样硬化的进展有不同的调节作用。我们研究了三组雄性载脂蛋白E基因敲除（ApoE(-/-)）小鼠：一组表达野生型TNF（WT-TNF）；一组只表达突变的不可裂解形式的TNF（KI-TNF）；一组缺乏TNF（KO-TNF）。5周龄的小鼠分别喂食高脂饮食5周（T5）和15周（T15），或标准普通饮食15周。在T5时，喂食高脂饮食的小鼠中，三组小鼠在瓣膜或主动脉中的病变面积均未观察到显著差异。在T15时，与WT-TNF小鼠相比，KO-TNF小鼠瓣膜中的病变面积显著降低，而在KI-TNF小鼠中，病变面积介于KO-TNF和WT-TNF小鼠之间，但与这两组无显著差异。在主动脉中，KI-TNF小鼠的病变与KO-TNF小鼠相当，两者均显著低于WT-TNF小鼠。这些差异与循环脂质、病变中的巨噬细胞、肌动蛋白和胶原蛋白含量无关。在T15时，喂食普通饮食的小鼠中，三组小鼠瓣膜和主动脉弓中的病变面积无显著差异。高脂饮食T15时，脾脏中白细胞介素-6（IL-6）、干扰素γ（IFNγ）、白细胞介素-10（IL-10）和叉头框蛋白3（Foxp3）mRNA水平以及腹膜巨噬细胞产生的IL-6、IL-10、单核细胞趋化蛋白-1（MCP-1）、调节激活正常T细胞表达和分泌因子（RANTES）和肿瘤坏死因子受体-2（TNFR-2）表明促炎状态降低，在KO-TNF小鼠中比在KI-TNF小鼠中更明显。仅在KO-TNF小鼠中细胞凋亡减少。总之，这些数据表明，TNF对动脉粥样硬化发展的影响在脂肪条纹之后的阶段是可检测到的，并且野生型TNF在促进动脉粥样硬化方面优于单独的tmTNF。TNF依赖性动脉粥样硬化的进展可能与促炎介质的差异产生有关，无论tmTNF是占优势还是基本上被裂解。
