Reifenberg Kurt, Cheng Fei, Twardowski Laura, Küpper Ines, Wiese Elena, Bollmann Franziska, Kleinert Hartmut, Blessing Manfred, Lackner Karl J, Torzewski Michael
Animal Laboratory Services, German Cancer Research Center, Heidelberg, Germany.
PLoS One. 2013 Dec 5;8(12):e81444. doi: 10.1371/journal.pone.0081444. eCollection 2013.
Clinical data have indicated a negative correlation between plasma TGFß1 concentrations and the extent of atherosclerosis and have thus led to the hypothesis that the pleiotropic cytokine may have anti-atherogenic properties. T-cells are currently discussed to significantly participate in atherogenesis, but the precise role of adaptive immunity in atherogenesis remains to be elucidated. TGFß1 is known to strongly modulate the function of T-cells, however, inhibition of TGFß1 signalling in T-cells of atherosclerosis-prone knock-out mice failed to unequivocally clarify the role of the cytokine for the development of atherosclerosis. In the present study, we thus tried to specify the role of TGFß1 in atherogenesis by using the murine CD2-TGFß1 transgenic strain which represents a well characterized model of T-cell specific TGFß1 overexpression. The CD2-TGFß1 transgenic mice were crossed to ApoE knock-out mice and quantity and quality of atherosclerosis regarding number of macrophages, smooth muscle cells, CD3 positive T-cells and collagen was analyzed in CD2-TGFß1 ApoE double mutants as well as non-transgenic ApoE controls on both normal and atherogenic diet of a duration of 8, 16 or 24 weeks, respectively. In all experimental groups investigated, we failed to detect any influence of TGFß1 overexpression on disease. Total number of CD3-positive T-lymphocytes was not significantly different in atherosclerotic lesions of CD2-TGFß1 ApoE(-/-) females and isogenic ApoE(-/-) controls, even after 24 weeks on the atherogenic diet. The synopsis of these data and our previous study on TGFß1 overexpressing macrophages suggests that potential effects of TGFß1 on atherosclerosis are most probably mediated by macrophages rather than T-cells.
临床数据表明血浆转化生长因子β1（TGFβ1）浓度与动脉粥样硬化程度呈负相关，因此提出了这种多效性细胞因子可能具有抗动脉粥样硬化特性的假说。目前认为T细胞在动脉粥样硬化发生过程中起重要作用，但适应性免疫在动脉粥样硬化发生中的具体作用仍有待阐明。已知TGFβ1能强烈调节T细胞功能，然而，在易患动脉粥样硬化的基因敲除小鼠的T细胞中抑制TGFβ1信号传导未能明确阐明该细胞因子在动脉粥样硬化发展中的作用。因此，在本研究中，我们试图通过使用小鼠CD2-TGFβ1转基因品系来明确TGFβ1在动脉粥样硬化发生中的作用，该品系是T细胞特异性TGFβ1过表达的一个特征明确的模型。将CD2-TGFβ1转基因小鼠与载脂蛋白E（ApoE）基因敲除小鼠杂交，分别在正常饮食和致动脉粥样硬化饮食条件下喂养8周、16周或24周，然后分析CD2-TGFβ1 ApoE双突变体以及非转基因ApoE对照小鼠中动脉粥样硬化的数量和质量，包括巨噬细胞、平滑肌细胞、CD3阳性T细胞和胶原蛋白的数量。在所有研究的实验组中，我们未能检测到TGFβ1过表达对疾病有任何影响。即使在致动脉粥样硬化饮食24周后，CD2-TGFβ1 ApoE（-/-）雌性小鼠和同基因ApoE（-/-）对照小鼠动脉粥样硬化病变中CD3阳性T淋巴细胞的总数也没有显著差异。这些数据以及我们之前关于TGFβ1过表达巨噬细胞的研究表明，TGFβ1对动脉粥样硬化的潜在影响很可能是由巨噬细胞而非T细胞介导的。
