Decreased atherosclerosis in mice deficient in tumor necrosis factor-alpha receptor-II (p75).

Tumor Necrosis FactorReceptor-II (p75) To the Editor: TNFinduces a wide variety of proatherogenic molecules,1 and inhibition of TNFin apoe / mice results in diminished atherosclerosis suggesting the involvement of TNFin atherogenesis.2,3 TNFelicits its effects by activating 2 cell-surface receptors, namely p55 and p75. Earlier, Blessing et al reported that apoe / mice lacking p55 fed a chow diet did not show altered lesion progression or plaque composition.4 Recently, we showed that p75 is required for TNF–induced leukocyte–endothelial cell interaction and inflammation in vivo.5 Because inflammation plays an integral role in atherogenesis, we tested whether the proatherogenic activity of TNFwas mediated by p75. We determined the role of p75 in atherogenesis using apoe / mice lacking p75 receptor. We generated p75 / :apoe / , p75 / :apoe / , and p75 / :apoe / by sister– brother mating of p75 / :apoe / parents. Atherosclerotic lesion areas in aortic roots were measured after staining with Oil red O in 16-week-old chow diet-fed female mice. As shown in the Figure, the p75 / :apoe / mice had a mean lesion area of 125 000 32 000 m (n 10). Lesion area in the hemizygous p75 / :apoe / mice was 116 000 48 000 (n 10), which was similar to that in the p75 / : apoe / mice, suggesting that one copy of the p75 gene is sufficient to promote its proatherosclerotic effect. The p75 / :apoe / mice had a mean lesion area of 72 000 28 000 m (n 10), representing a 43% reduction in lesion area compared with the p75 / :apoe / mice (P 0.01), and a 37% decrease compared with the p75 / :apoe / mice (P 0.05). Body weights, lipid composition, and total plasma cholesterol were similar in the p75 / :apoe / and p75 / :apoe / genotypes. Our results are not consistent with the earlier observation by Schreyer et al in which the lack of p75 did not alter atherosclerosis development.6 However, this group used a distinct model, in which C57BL/6 mice were fed a high-fat, high-cholesterol, cholatecontaining diet. The apoe / model is more robust, yielding larger lesions in a shorter time period.7 Our results indicate that the proatherogenic effect of TNFis primarily mediated via the activation of p75 in apoe / mice. We wished to determine whether p75 activity shifts the homeostasis of cytokine production toward an inflammatory phenotype. We used a Multiplex assay system (LINCOplex kit, Linco Research Inc) to measure 22 cytokines from the plasma of individual chow-fed female p75 / :apoe / (n 4) and p75 / :apoe / mice (n 4) mice at 16 weeks of age. As shown in the Table, we identified significant increases in the levels of TNFand interleukin (IL)-17 (both are proinflammatory cytokines), and in the levels of the antiinflammatory cytokine IL-10 in the p75 / :apoe / mice. The TNFlevel was elevated 2.2-fold, the IL-17 level was elevated 2.0fold, and the IL-10 level was elevated by 1.8-fold in the p75 / :apoe / mice compared with p75 / :apoe / mice. Furthermore, we identified a significant 42% decrease in the plasma level of the proinflammatory cytokine IL-1 in the p75 / :apoe / mice. The plasma levels of TNF, IL-17, IL, and IL-10 were undetectable in the age-matched p75 / :apoe / mice, suggesting that the lack of the apoE gene caused an upregulation of TNF, IL-17, IL, and IL-10 with p75 having a regulatory role in the process. Because p75 / :apoe / mice developed smaller atherosclerotic lesions than p75 / :apoe / mice, it is possible that the upregulation of IL-10 accompanied by the downregulation of IL-1 could override the proinflammatory activity of IL-17 in the p75 / :apoe / mice. In conclusion, we have demonstrated that TNFreceptor p75deficiency in apoe / mice reduced atherosclerotic lesion development in the aortic root. This reduction in the lesion size is associated with altered plasma cytokine production, but without an effect on plasma cholesterol levels.