title: Interleukin-12p35 deletion promotes CD4 T-cell-dependent macrophage differentiation and enhances angiotensin II-Induced cardiac fibrosis.
abstract: 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.
  
  
  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.
authors.affiliation: Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.forename: Congcong
authors.initials: C
authors.lastname: Zhang
authors.forename: Yina
authors.initials: Y
authors.lastname: Wu
authors.forename: Yalei
authors.initials: Y
authors.lastname: Han
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Lixin
authors.initials: L
authors.lastname: Jia
authors.forename: Lun
authors.initials: L
authors.lastname: Cai
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation; D016764:Cell Polarity; D002478:Cells, Cultured; D005355:Fibrosis; D053765:Interleukin-12 Subunit p35 / Q000502:physiology*; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D053765:Interleukin-12 Subunit p35; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D000804:Angiotensin II