Bcl2-Like Protein 12 Is Required for the Aberrant T Helper-2 Polarization in the Heart by Enhancing Interleukin-4 Expression and Compromising Apoptotic Machinery in CD4+ T Cells.

Abstract

BACKGROUND:

The biased T helper-2 (Th2) response plays a critical role in myocarditis. Bcl2-like protein 12 (Bcl2L12) is associated with the Th2 pattern of inflammation. This study aims to elucidate the role of Bcl2L12 in the pathogenesis of Th2-biased inflammation in the heart.

METHODS:

Mice were treated with the myosin heavy-chain-α peptides to induce inflammation in the heart. Human hearts were collected from the surgically removed hearts of patients who had undergone heart transplantation.

RESULTS:

The expression of Bcl2L12 was detected in CD4+ T cells of the hearts, which was markedly higher in the hearts with myocarditis at the advanced stage of heart failure compared with the control (dilated cardiomyopathy) hearts without myocarditis. Mice with Bcl2L12-deficient CD4+ T cells failed to induce the Th2-biased inflammation in the heart. CD4+ T cells with a higher expression of Bcl2L12 were prone to differentiate into Th2 cells. Bcl2L12 formed a complex with GATA3 in CD4+ T cells to enhance the binding between GATA3 and the Il4 promoter, which promoted the Il4 gene transcription. Bcl2L12 compromised the apoptotic machinery by inhibiting the expression of p53 in CD4+ T cells to reduce the activation-induced CD4+ T cell death.

CONCLUSIONS:

CD4+ T cells isolated from hearts with myocarditis at the end stage of heart failure express high levels of Bcl2L12, and the latter is required for the development of aberrant Th2 polarization in the heart. The Bcl2L12 may be a novel target in the treatment of myocarditis as well as other Th2-biased inflammation.

• Authors: Xiao Chen, Xian-Hai Zeng, Mangyuan Wang, Liang Chen, Ningning Zhang, Man Rao, Ping-Chang Yang, Jiangping Song
• Journal: Circulation (Circulation) Vol. 138 Issue 22 Pg. 2559-2568 (11 27 2018) ISSN: 1524-4539 [Electronic] United States
• PMID: 30571346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bcl2l12 protein, mouse
• Cytokines
• GATA3 Transcription Factor
• Gata3 protein, mouse
• Proto-Oncogene Proteins c-bcl-2
• Trp53 protein, mouse
• Tumor Suppressor Protein p53
• Interleukin-4

Topics

• Adult
• Animals
• Apoptosis
• CD4-Positive T-Lymphocytes (cytology, immunology, metabolism)
• Cardiomyopathy, Dilated (metabolism, pathology)
• Cytokines (genetics, metabolism)
• Female
• GATA3 Transcription Factor (metabolism)
• Humans
• Interleukin-4 (genetics, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Myocarditis (metabolism, pathology)
• Myocardium (cytology, immunology, metabolism)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Th2 Cells (cytology, immunology, metabolism)
• Tumor Suppressor Protein p53 (metabolism)