title: Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis.
abstract: We aimed to explore the effects of bromodomain-containing protein 4 (BRD4) inhibition on tumor necrosis factor (TNF)-α-stimulated human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) behavior and the therapeutic implications using BRD4 inhibitor JQ1 were explored in vivo. The levels of interleukin (IL)-1β, IL-6, IL-17 and IL-18 in cultural supernatants from TNFα-stimulated RA-FLS were measured by ELISA. RA-FLS migration and invasion in vitro were investigated using wound healing and Matrigel assay. Expression of signaling pathway proteins was measured by Western blot. The in vivo effects of BRD4 inhibitor JQ1 were elucidated using collagen-induced arthritis (CIA) mice. We found BRD4 silencing reduced the secretion of IL-1β, IL-6, IL-17 and IL-18 from TNFα-stimulated human RA-FLS. Downregulation of BRD4 inhibited FBS-induced migration and invasion of human RA-FLS. BRD4 silencing decreased the phosphorylation of c-Jun and activation of NFκB in TNFα-stimulated RA-FLS. In vivo, BRD4 inhibitor JQ1 reduced the inflammatory response, autoantibody production and joint damage of CIA model. Our data suggest for the first time that BRD4 inhibition has anti-inflammatory property in RA.
authors.affiliation: Department of Orthopaedics, Tenth People's Hospital of Tongji University, 301 Yanchang Middle Road, Shanghai 200072, PR China.
authors.forename: Qing-gang
authors.initials: QG
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, Tenth People's Hospital of Tongji University, 301 Yanchang Middle Road, Shanghai 200072, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Orthopaedics, Tenth People's Hospital of Tongji University, 301 Yanchang Middle Road, Shanghai 200072, PR China. Electronic address: yuchangzhu@yeah.net.
authors.forename: Yu-chang
authors.initials: YC
authors.lastname: Zhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D003175:Complement C2 / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001323:Autoantibodies; D001381:Azepines; D018797:Cell Cycle Proteins; D003175:Complement C2; D016207:Cytokines; D018836:Inflammation Mediators; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: Bromodomain-containing protein 4 (BRD4); Collagen-induced arthritis; Fibroblast-like synoviocytes; Gene silencing; JQ1; Rheumatoid arthritis