Interleukin-12p35 Deletion Promotes CD4 T-Cell–Dependent Macrophage Differentiation and Enhances Angiotensin II–Induced Cardiac Fibrosis

• DOI: 10.1161/atvbaha.112.249706
• Publication Date: 2012-05-04T05:52:27Z
• Authors: Yulin Li; Congcong Zhang; Yina Wu; Yalei Han; Wei Cui; Lixin Jia; Lun Cai; Jizhong Cheng; Huihua Li; Jie Du
• Keywords: CD4-Positive T-Lymphocytes; Male; 0301 basic medicine; Angiotensin II; Macrophages; Myocardium; NF-kappa B; Cell Polarity; Cell Differentiation; Fibrosis; Interleukin-12 Subunit p35; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Transforming Growth Factor beta; Animals; Cells, Cultured; Signal Transduction

Objective— Interleukin-12 is essential for the differentiation of naïve T cells into interferon-γ–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-β. Moreover, CD4 + T-cell–treated p35-KO macrophages could stimulate cardiac fibroblasts to differentiate into α-smooth muscle actin–positive and collagen I–positive myofibroblasts in 3-dimensional nanofiber gels. Neutralizing antibodies against transforming growth factor-β 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-β.