Ubiquitin‐activating enzyme E 1 inhibitor PYR 41 attenuates angiotensin II ‐induced activation of dendritic cells via the I κ B a/ NF ‐ κ B and MKP 1/ ERK / STAT 1 pathways

Summary The activation of dendritic cells ( DC s) is necessary to initiate immune responses. Angiotensin II ( A ng  II ) can enhance the maturation and activation of DC s, but the mechanisms are still unclear. Ubiquitin‐activating enzyme ( E 1/ U ba1) 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 E 1 in A ng  II ‐induced activation of DC s and the underlying mechanisms. First, we showed that A ng  II stimulation significantly up‐regulated E 1 expression in DC s. Moreover, A ng  II treatment markedly induced phenotypic maturation, the secretion of cytokines and the immunostimulatory capacity of DC s. In contrast, inhibition of E 1 by a small molecule inhibitor, 4 [4‐(5‐nitro‐furan‐2‐ylmethylene)‐3, 5‐dioxo‐pyrazolidin‐1‐yl]‐benzoic acid ethyl ester ( PYR 41), markedly attenuated these effects. Mechanistically, PYR 41 treatment markedly decreased K 63‐linked ubiquitination of tumour necrosis factor receptor‐associated factor 6 and nuclear factor‐ κ B essential modulator, inhibited proteasomal degradation of nuclear factor‐ κ B inhibitor α and mitogen‐activated protein kinase phosphatase 1 thereby resulting in activation of nuclear factor‐ κ B , extracellular signal‐regulated kinase 1/2 and signal transducer and activator of transcription 1 signalling pathways in DC s induced by A ng  II . Taken together, our results demonstrate a novel role of E 1 in A ng  II ‐induced activation of DC s, and inhibition of E 1 activity might be a potential therapeutic target for DC ‐mediated autoimmune diseases.