title: Therapeutic targeting of BET protein BRD4 delays murine lupus.
abstract: BRD4 is a member of the BET (bromodomain and extraterminal domain) family proteins that can bind acetylated histones and influence transcription, which are considered as potential therapeutic targets in many distinct diseases. And the BET inhibitor JQ1 has been proven to be effective in suppressing multiple inflammatory and autoimmune diseases. This study aimed to examine the therapeutic potential of JQ1 on a lupus model, MRL-lpr mice. Ten-week-old MRL-lpr mice were treated with JQ1 (oral administration of 200mg/kg) or vehicle for 8weeks. The proteinuria, nephritic damage, serum biochemistry, autoantibodies and cytokines were examined. Splenocytes of MRL-lpr mice were isolated for in vitro experiments. Treatment with JQ1 significantly attenuated the progression of proteinuria and nephritis. The serum concentrations of anti-dsDNA antibody as well as B-cell activating factor (BAFF), interleukin (IL)-1β, IL-6, IL-17 and INF-γ were inhibited, and IL-10 augmented by JQ1. Importantly, JQ1 improved the survival of lupus mice. In vitro, BAFF, IL-1β, IL-6, IL-17 and INF-γ were inhibited, and IL-10 augmented by JQ1 (500nM) in the cultures of splenocytes from diseased MRL-lpr mice, which was further supported by a significant reduction in immune complex-mediated activation of human monocytes in vitro by JQ1. Taken together, JQ1 effectively alleviates lupus in MRL-lpr mice by suppressing BAFF, pro-inflammatory cytokines and autoimmunity, supporting the therapeutic value of JQ1 in lupus disease.
authors.affiliation: Department of Rheumatology, Yantai Yantaishan Hospital, Yantai 264000, China.
authors.forename: Shitong
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Rheumatology, Yantai Yantaishan Hospital, Yantai 264000, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Drug Supply, Yantai Yuhuangding Hospital, Yantai 264000, China. Electronic address: yushahong88@163.com.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Sha
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D004247:DNA / Q000187:drug effects / Q000276:immunology; D018450:Disease Progression; D006801:Humans; D007668:Kidney / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008181:Lupus Nephritis / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009000:Monocytes / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D009687:Nuclear Proteins / Q000187:drug effects*; D011507:Proteinuria / Q000473:pathology / Q000517:prevention & control; D011956:Receptors, Cell Surface / Q000187:drug effects*; D013154:Spleen / Q000473:pathology; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D004247:DNA; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C486765:Dner protein, mouse; C022616:thiazolyl blue
keywords: BET proteins; BRD4; JQ1; Systemic lupus erythematosus