Li Yuan1, Xiao Chen1, Liang Cheng1, Man Rao1, Kai Chen1, Ningning Zhang1, Jian Meng1, Mengmeng Li1, Li-Tao Yang2, Ping-Chang Yang3, Xin Wang1, Jiangping Song4. 1. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Beijing 100037, China. 2. Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen 518055, China; Brain Body Institute, McMaster University, Hamilton, ON L8N 4A6, Canada. 3. Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen 518055, China. 4. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Beijing 100037, China. Electronic address: fwsongjiangping@hotmail.com.
Abstract
BACKGROUND AND AIMS: Immune deregulation is a causative factor in pathogenesis of myocarditis. Histone deacetylases (HDAC) involve multiple biochemical activities in the cell. This study aims to elucidate the role of HDAC11 in the regulation of interleukin (IL)-13-expression in CD4+ T cells of heart tissue in patients with myocarditis (MCD). METHODS: After heart transplantation, surgically removed hearts were collected from patients with advanced heart failure and MCD or dilated cardiomyopathy (DCM). CD4+ T cells were isolated from the heart samples and analyzed by immune assay. The association between IL-13 over production by CD4+ T cells in heart tissue and the pathogenesis of MCD was analyzed. RESULTS: T helper (Th) 2-biased inflammation was observed in hearts tissue of MCD patients with advanced heart failure. CD4+ T cells isolated from MCD heart tissue showed lower levels of HDAC11 expression than that isolated from DCM heart tissue. HDAC11 was negatively correlated with IL-13 expression in the CD4+ T cells. A complex of HDAC11 and E4 binding protein-4 (E4BP4; the transcription factor of IL13) was detected in the CD4+ T cells, which restricted the binding between E4BP4 and the Il13 promoter to repress the Il13 gene transcription. Reconstitution of HDAC11 in MCD CD4+ T cells reduced the expression of IL-13, while inhibition of HDAC11 in DCM CD4+ T cells increased the IL-13 expression. CONCLUSIONS: HDAC11 is a regulatory molecule in Th2 response and plays a critical role in the restriction of the biased IL-13 expression in CD4+ T cells of the heart.
BACKGROUND AND AIMS: Immune deregulation is a causative factor in pathogenesis of myocarditis. Histone deacetylases (HDAC) involve multiple biochemical activities in the cell. This study aims to elucidate the role of HDAC11 in the regulation of interleukin (IL)-13-expression in CD4+ T cells of heart tissue in patients with myocarditis (MCD). METHODS: After heart transplantation, surgically removed hearts were collected from patients with advanced heart failure and MCD or dilated cardiomyopathy (DCM). CD4+ T cells were isolated from the heart samples and analyzed by immune assay. The association between IL-13 over production by CD4+ T cells in heart tissue and the pathogenesis of MCD was analyzed. RESULTS: T helper (Th) 2-biased inflammation was observed in hearts tissue of MCDpatients with advanced heart failure. CD4+ T cells isolated from MCD heart tissue showed lower levels of HDAC11 expression than that isolated from DCM heart tissue. HDAC11 was negatively correlated with IL-13 expression in the CD4+ T cells. A complex of HDAC11 and E4 binding protein-4 (E4BP4; the transcription factor of IL13) was detected in the CD4+ T cells, which restricted the binding between E4BP4 and the Il13 promoter to repress the Il13 gene transcription. Reconstitution of HDAC11 in MCD CD4+ T cells reduced the expression of IL-13, while inhibition of HDAC11 in DCM CD4+ T cells increased the IL-13 expression. CONCLUSIONS:HDAC11 is a regulatory molecule in Th2 response and plays a critical role in the restriction of the biased IL-13 expression in CD4+ T cells of the heart.