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- Title
Chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of USP25.
- Authors
Ding, Changyu; Li, Fangfang; Long, Yupeng; Zheng, Jiang
- Abstract
Lipopolysaccharide (LPS) is a key pathogenic factor in sepsis, and its recognition by toll-like receptor 4 (TLR4) can activate two district signaling pathways, leading to activation of transcription factors including NF-κB and interferon regulatory factor 3 (IRF3). Chloroquine (CQ) has been shown to affect LPS-TLR4 colocalization and inhibit both MyD88-dependent and TRAM/TRIF-dependent pathways, though the mechanism involved is still poorly understood. Here, we found that the ubiquitin-proteasome system might be involved in this process. CQ increased USP25, a deubiquitinating enzyme, as well as mRNA and protein expression in a dose-dependent manner, which might to some degree be involved in CQ attenuation of LPS-induced macrophage activation. Overexpression of USP25 decreased LPS-induced inflammatory cytokines like TNF-α, IL-6, and IFN-β, while specific siRNA-mediated USP25 silencing increased TNF-α, IL-6, and IFN-β production and secretion. In addition, USP25 deletion strengthened mitogen-activated protein kinase (MAPKs) phosphorylation and IκB degradation. Moreover, USP25 interference increased NF-κB and IRF3 nuclear translocation. Taken together, our data demonstrated a new possible regulator of LPS-induced macrophage activation mediated by CQ, through upregulation of USP25.
- Subjects
CHLOROQUINE; NF-kappa B; SEPSIS; UBIQUITIN; PROTEOLYTIC enzymes; LIPOPOLYSACCHARIDES
- Publication
Canadian Journal of Physiology & Pharmacology, 2017, Vol 95, Issue 5, p481
- ISSN
0008-4212
- Publication type
Article
- DOI
10.1139/cjpp-2016-0303