title: Chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of USP25.
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.
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.|Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.
authors.forename: Changyu
authors.initials: C
authors.lastname: Ding
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.|Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Li
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.|Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Long
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.|Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D020672:I-kappa B Proteins; C551354:IkappaBeta protein, mouse; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051996:Transcription Factor RelA; C000603994:USP25 protein, mouse; D002738:Chloroquine; D020928:Mitogen-Activated Protein Kinases; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
keywords: LPS; NF-κB; chloroquine; protéase spécifique à l’ubiquitine 25; sepsie; sepsis; ubiquitin-specific protease 25