Ubiquitin-activating enzyme E1 inhibitor PYR41 attenuates angiotensin II-induced activation of dendritic cells via the IκBa/NF-κB and MKP1/ERK/STAT1 pathways.
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.
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.
Chen
C
Chen
Yan
Y
Meng
Lei
L
Wang
Hong-Xia
HX
Wang
Cui
C
Tian
Guo-Dong
GD
Pang
Hui-Hua
HH
Li
Jie
J
Du
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005663:Furans; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors* / Q000276:immunology
C523934:4(4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl)-benzoic acid ethyl ester; D001565:Benzoates; D004791:Enzyme Inhibitors; D005663:Furans; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011720:Pyrazoles; D050794:STAT1 Transcription Factor; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D044764:Ubiquitin-Activating Enzymes
angiotensin II; cardiovascular disease; dendritic cells; inflammation; ubiquitin-activating enzyme E1