Nuclear receptor coactivator 3 transactivates proinflammatory cytokines in collagen-induced arthritis. (January 2023)

• Record Type: Journal Article
• Authors: Sun, Xiangxiang; Chen, Juan; Chen, Xinlin; Ma, Jianbing; Xiao, Lin; Yao, Shuxin; Dang, Xiaoqian
• Is Part Of: Cytokine. Volume 161(2023)
• Publication Date: 2023-01
• Subjects: NCOA3 -- P300 -- NF-κB -- Collagen-induced arthritis -- Proinflammatory cytokine; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2022.156074
• Languages: English
• ISSNs: 1043-4666

Abstract

Highlights: NCOA3 was overexpressed in the joint tissues of type II collagen-induced arthritis. The administration of two NCOA3 inhibitors significantly alleviated inflammation and improved the outcomes of CIA mice. NCOA3 assembled a transcriptional complex with p300 and NF-κB subunits and this complex specifically controlled the expression of proinflammatory cytokine genes by binding to their promoters. Abstract: Rheumatoid arthritis (RA) is an autoimmune disorder in which the immune system mistakenly attacks joints. The molecular mechanisms underlying RA pathology are still under investigation. In this study, we discovered overexpression of nuclear receptor coactivator 3 (NCOA3) in the joint tissues of type II collagen-induced arthritis (CIA) mice, an important autoimmune model of human RA. Administration of two NCOA3 inhibitors, gossypol (GSP) and SI-2 hydrochloride (SHC), significantly alleviated inflammation and improved the outcomes of CIA mice. In vivo and in vitro experiments revealed that NCOA3 assembled a transcriptional complex with a histone acetyltransferase p300 and two subunits of nuclear factor kappa B (NF-κB). This complex specifically controlled the expression of proinflammatory cytokine genes by binding to their promoters. Knockdown of NCOA3 or in vitro treatments with GSP and SHC impaired the assembly of NCOA3-p300-NF-κB complex and decreased the expression of proinflammatory cytokine genes. Taken together, our results demonstrated that NCOA3 acts as a mediator of proinflammatory cytokine genes in CIA mice and that inhibition of the NCOA3-p300-NF-κB complex may represent a new avenue for improving RA outcomes.