title: Vorinostat Modulates the Imbalance of T Cell Subsets, Suppresses Macrophage Activity, and Ameliorates Experimental Autoimmune Uveoretinitis.
abstract: The purpose of the study was to investigate the anti-inflammatory efficiency of vorinostat, a histone deacetylase inhibitor, in experimental autoimmune uveitis (EAU). EAU was induced in female C57BL/6J mice immunized with interphotoreceptor retinoid-binding protein peptide. Vorinostat or the control treatment, phosphate-buffered saline, was administrated orally from 3 days before immunization until euthanasia at day 21 after immunization. The clinical and histopathological scores of mice were graded, and the integrity of the blood-retinal barrier was examined by Evans blue staining. T helper cell subsets were measured by flow cytometry, and the macrophage functions were evaluated with immunohistochemistry staining and immunofluorescence assays. The mRNA levels of tight junction proteins were measured by qRT-PCR. The expression levels of intraocular cytokines and transcription factors were examined by western blotting. Vorinostat relieved both clinical and histopathological manifestations of EAU in our mouse model, and the BRB integrity was maintained in vorinostat-treated mice, which had less vasculature leakage and higher mRNA and protein expressions of tight junction proteins than controls. Moreover, vorinostat repressed Th1 and Th17 cells and increased Th0 and Treg cells. Additionally, the INF-γ and IL-17A expression levels were significantly decreased, while the IL-10 level was increased by vorinostat treatment. Furthermore, due to the reduced TNF-α level, the macrophage activity was considerably inhibited in EAU mice. Finally, transcription factors, including STAT1, STAT3, and p65, were greatly suppressed by vorinostat treatment. Our data suggest that vorinostat might be a potential anti-inflammatory agent in the management of uveitis and other autoimmune inflammatory diseases.
authors.affiliation: Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, China.
authors.forename: Sijie
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, China.
authors.forename: Xiangda
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, China.
authors.forename: Zhuhong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, China.
authors.forename: Caiyun
authors.initials: C
authors.lastname: You
authors.affiliation: Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, China. phuayan2000@163.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Yan
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D001813:Blood-Retinal Barrier; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D005136:Eye Proteins / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D012173:Retinitis / Q000188:drug therapy* / Q000276:immunology; D012177:Retinol-Binding Proteins / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D019108:Tight Junctions / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology; D000077337:Vorinostat; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D001324:Autoantigens; D016207:Cytokines; D005136:Eye Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D012177:Retinol-Binding Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat; D000099214:Retinol-Binding Proteins, Interstitial
keywords: Experimental autoimmune uveitis; NF-κB; STAT; T lymphocyte; Vorinostat