Interleukin-12p35 deletion promotes CD4 T-cell-dependent macrophage differentiation and enhances angiotensin II-Induced cardiac fibrosis

Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1662-74. doi: 10.1161/ATVBAHA.112.249706. Epub 2012 May 3.


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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • CD4-Positive T-Lymphocytes / physiology*
  • Cell Differentiation*
  • Cell Polarity
  • Cells, Cultured
  • Fibrosis
  • Interleukin-12 Subunit p35 / physiology*
  • Macrophages / cytology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / pathology*
  • NF-kappa B / physiology
  • Signal Transduction
  • Transforming Growth Factor beta / physiology


  • Interleukin-12 Subunit p35
  • NF-kappa B
  • Transforming Growth Factor beta
  • Angiotensin II