Ubiquitin-activating enzyme E1 inhibitor PYR41 attenuates angiotensin II-induced activation of dendritic cells via the IκBa/NF-κB and MKP1/ERK/STAT1 pathways

Authors

  • Chen Chen,

    1. Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, The Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing, China
    Search for more papers by this author
  • Yan Meng,

    1. Department of Physiology and Pathophysiology, Capital Medical University, Beijing, China
    Search for more papers by this author
  • Lei Wang,

    1. Department of Physiology and Pathophysiology, Capital Medical University, Beijing, China
    Search for more papers by this author
  • Hong-Xia Wang,

    1. Department of Physiology and Pathophysiology, Capital Medical University, Beijing, China
    Search for more papers by this author
  • Cui Tian,

    1. Department of Physiology and Pathophysiology, Capital Medical University, Beijing, China
    Search for more papers by this author
  • Guo-Dong Pang,

    1. Department of Physiology and Pathophysiology, Capital Medical University, Beijing, China
    Search for more papers by this author
  • Hui-Hua Li,

    Corresponding author
    1. Department of Physiology and Pathophysiology, Capital Medical University, Beijing, China
    • Correspondence: Jie Du, Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, The Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing 100029, China. Email: jdu@bcm.edu

      Or

      Hui-Hua Li, Department of Physiology and Pathophysiology, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, China. Email: hhli1995@yahoo.com

      Senior author: Jie Du and Hui-Hua Li

    Search for more papers by this author
  • Jie Du

    Corresponding author
    1. Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, The Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing, China
    • Correspondence: Jie Du, Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, The Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing 100029, China. Email: jdu@bcm.edu

      Or

      Hui-Hua Li, Department of Physiology and Pathophysiology, Capital Medical University, No. 10 Xitoutiao, You An Men, Beijing 100069, China. Email: hhli1995@yahoo.com

      Senior author: Jie Du and Hui-Hua Li

    Search for more papers by this author

Summary

The activation of dendritic cells (DCs) is necessary to initiate immune responses. Angiotensin II (Ang II) can enhance the maturation and activation of DCs, but the mechanisms are still unclear. Ubiquitin-activating enzyme (E1/Uba1) is the common first step in ubiquitylation, which decides whether or not the modified protein is ultimately degraded by the proteasome. This study aimed to investigate the role of E1 in Ang II-induced activation of DCs and the underlying mechanisms. First, we showed that Ang II stimulation significantly up-regulated E1 expression in DCs. Moreover, Ang II treatment markedly induced phenotypic maturation, the secretion of cytokines and the immunostimulatory capacity of DCs. In contrast, inhibition of E1 by a small molecule inhibitor, 4 [4-(5-nitro-furan-2-ylmethylene)-3, 5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR41), markedly attenuated these effects. Mechanistically, PYR41 treatment markedly decreased K63-linked ubiquitination of tumour necrosis factor receptor-associated factor 6 and nuclear factor-κB essential modulator, inhibited proteasomal degradation of nuclear factor-κB inhibitor α and mitogen-activated protein kinase phosphatase 1 thereby resulting in activation of nuclear factor-κB, extracellular signal-regulated kinase 1/2 and signal transducer and activator of transcription 1 signalling pathways in DCs induced by Ang II. Taken together, our results demonstrate a novel role of E1 in Ang II-induced activation of DCs, and inhibition of E1 activity might be a potential therapeutic target for DC-mediated autoimmune diseases.

Ancillary