Interleukin-12p35 Deletion Promotes CD4 T-Cell-Dependent Macrophage Differentiation and Enhances Angiotensin II-Induced Cardiac Fibrosis
Interleukin-12p35 Deletion Promotes CD4 T-Cell-Dependent Macrophage Differentiation and Enhances Angiotensin II-Induced Cardiac Fibrosis
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Interleukin-12p35 缺失促进 CD4 T 细胞依赖性巨噬细胞分化并增强血管紧张素 II 诱导的心脏纤维化
DOI：
10.1161/atvbaha.112.249706
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发表时间：
2012-07-01
影响因子：
8.7
通讯作者：
Du, Jie
中科院分区：
文献类型：
--
作者：
Li, Yulin;Zhang, Congcong;Du, Jie
目的-白细胞介素-12对于幼稚T细胞分化为产生干扰素γ的T细胞至关重要，从而调节炎症反应。我们研究了这一过程中的调节高血压引起的cardiac fibrosis.Methods和Results-Mice注入血管紧张素II显示了心脏巨噬细胞中白细胞介素-12p35的表达显着增加。与野生型（WT）同窝小鼠相比，白细胞介素12 p35敲除（p35-KO）小鼠对血管紧张素II的反应性心脏纤维化程度显著增强。p35-KO小鼠的纤维化心脏显示出交替激活（M2）巨噬细胞的积累增加和M2基因（如Arg-1和Fizz 1）的表达增加。WT或p35-KO小鼠的骨髓源性巨噬细胞对血管紧张素II治疗的反应在分化方面没有差异;然而，在存在CD 4（+）T细胞的情况下，p35-KO小鼠的巨噬细胞分化为M2巨噬细胞，并显示转化生长因子-β的表达升高。此外，CD 4（+）T细胞处理的p35-KO巨噬细胞可以刺激心脏成纤维细胞分化为α-平滑肌肌动蛋白阳性和胶原I阳性的肌成纤维细胞在三维凝胶。针对转化生长因子-β的中和抗体抑制了M2 macrophages. Conclusion-deficiency in interleukin-12 p35通过促进CD 4（+）T细胞依赖性分化M2 macrophages和转化生长因子-β的产生调节血管紧张素II诱导的心脏纤维化。（Arterioscler Thromb Vasc Biol 2012;32：1662-1674.）
Objective-Interleukin-12 is essential for the differentiation of naive T cells into interferon-gamma-producing T cells, which regulate inflammatory responses. We investigated this process of regulating hypertension-induced cardiac fibrosis.Methods and Results-Mice infused with angiotensin II showed a marked increase in interleukin-12p35 expression in cardiac macrophages. The degree of cardiac fibrosis was significantly enhanced in interleukin-12p35 knockout (p35-KO) mice compared with wild-type (WT) littermates in response to angiotensin II. Fibrotic hearts of p35-KO mice showed increased accumulation of alternatively activated (M2) macrophages and expression of M2 genes such as Arg-1 and Fizz1. Bone marrow-derived macrophages from WT or p35-KO mice did not differ in differentiation in response to angiotensin II treatment; however, in the presence of CD4(+) T cells, macrophages from p35-KO mice differentiated into M2 macrophages and showed elevated expression of transforming growth factor-beta. Moreover, CD4(+) T-cell-treated p35-KO macrophages could stimulate cardiac fibroblasts to differentiate into alpha-smooth muscle actin-positive and collagen I-positive myofibroblasts in 3-dimensional nanofiber gels. Neutralizing antibodies against transforming growth factor-beta inhibited myofibroblast formation induced by M2 macrophages.Conclusion-Deficiency in interleukin-12p35 regulates angiotensin II-induced cardiac fibrosis by promoting CD4(+) T-cell-dependent differentiation of M2 macrophages and production of transforming growth factor-beta. (Arterioscler Thromb Vasc Biol 2012;32:1662-1674.)