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Silencing of STAT4 Protects Against Autoimmune Myocarditis by Regulating Th1/Th2 Immune Response via Inactivation of the NF-κB Pathway in Rats

  • Yu-Long Xue
  • Sheng-Xiao Zhang
  • Chao-Feng Zheng
  • Yu-Feng Li
  • Li-Hui Zhang
  • Yu-Fei Hao
  • Shu Wang
  • Xue-Wen LiEmail author


Signal transducer and activator of transcription 4 (STAT4) has been implicated in the progression of myocarditis. The aim of the current study was to investigate the role by which STAT4 influences autoimmune myocarditis in an attempt to identify a theoretical therapeutic perspective for the condition. After successful establishment of an autoimmune myocarditis rat model, the expression patterns of STAT4, NF-κB pathway–related genes, Th1 inflammatory cytokines (IFN-γ and IL-2), and Th2 inflammatory cytokines (IL-6 and IL-10) were subsequently determined. The rats with autoimmune myocarditis were treated with oe-STAT4 or sh-STAT4 lentiviral vectors to evaluate the role of STAT4 in autoimmune myocarditis, or administrated with 1 mL 10 μmol/L of BAY11-7082 (the NF-κB pathway inhibitor) via tail vein to investigate the effect of the NF-κB pathway on autoimmune myocarditis. Finally, cell apoptosis was evaluated. The serum levels of IFN-γ and IL-2, extent of IκBα and P65 phosphorylation, and the expression of STAT4 were elevated, while the serum levels of IL-6 and IL-10 as well as the expression of IκBα were reduced among the rats with autoimmune myocarditis, which was accompanied by an increase in the apoptotic cells. More importantly, the silencing of STAT4 or the inhibition of the NF-κB pathway was detected to result in a decrease in the serum levels of IFN-γ and IL-2 and an elevation of the serum levels of IL-6 and IL-10, and inhibited myocardial cell apoptosis in rats with autoimmune myocarditis. Moreover, STAT4 silencing was also observed to decrease the extent of IκBα and P65 phosphorylation while acting to elevate the expression of IκBα. Taken together, silencing of STAT4 could hinder the progression of autoimmune myocarditis by balancing the expression of Th1/Th2 inflammatory cytokines via the NF-κB pathway, which may provide a novel target for experimental autoimmune myocarditis (EAM) treatment.

Key Words

signal transducer and activator of transcription 4 NF-κB pathway autoimmune myocarditis Th1/2 cytokines 



We acknowledge and appreciate our colleagues for their valuable efforts and comments on this paper.

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no conflict of interest.

Supplementary material

10753_2019_978_MOESM1_ESM.png (175 kb)
ESM 1 (PNG 174 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yu-Long Xue
    • 1
  • Sheng-Xiao Zhang
    • 2
  • Chao-Feng Zheng
    • 3
  • Yu-Feng Li
    • 4
  • Li-Hui Zhang
    • 1
  • Yu-Fei Hao
    • 2
  • Shu Wang
    • 5
  • Xue-Wen Li
    • 1
    Email author
  1. 1.Department of Cardiovascular MedicineShanxi Dayi Hospital Affiliated to Shanxi Medical UniversityTaiyuanPeople’s Republic of China
  2. 2.Department of RheumatologyThe Second Hospital of Shanxi Medical UniversityTaiyuanPeople’s Republic of China
  3. 3.Genetics LaboratoryLinfen Meternity & Child Healthcare HospitalLinfenPeople’s Republic of China
  4. 4.Department of Neurology and Stroke CenterThe First Affiliated Hospital of Jinan UniversityGuangzhouPeople’s Republic of China
  5. 5.Department of Rehabilitation MedicineThe First Affiliated Hospital of Xiamen UniversityXiamenPeople’s Republic of China

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