title: Roseotoxin B Improves Allergic Contact Dermatitis through a Unique Anti-Inflammatory Mechanism Involving Excessive Activation of Autophagy in Activated T Lymphocytes.
abstract: An immunosuppressant agent with negligible or acceptable toxicity may provide a better therapeutic strategy for treatment of allergic contact dermatitis. We identified a natural cyclopeptide, roseotoxin B, that effectively suppressed cell proliferation and the production of proinflammatory cytokines in activated T cells but exhibited little naive T-cell toxicity at concentrations of 0.3-1 μmol/L. In addition, roseotoxin B inhibited the activation of AKT and signal transducer and activator of transcription-3, suppressed cell cycle-related signaling, caused G0/G1 phase arrest, reduced ribosomal protein-S3 (RPS3)-dependent NF-κB-mediated IL-2 production, and increased autophagy in activated T cells. Furthermore, picryl chloride-induced allergic contact dermatitis was significantly ameliorated by roseotoxin B in mice. The effects of roseotoxin B were inhibited in LC3-knockout mice, indicating that roseotoxin B acts in an autophagy-dependent manner in T-cell-mediated skin diseases. Overall, this study showed a mechanism for roseotoxin B-induced autophagic cell death and provided a unique perspective on autophagy-mediated down-regulation of NF-κB signaling in activated T cells. The unique anti-inflammatory mechanism of roseotoxin B against activated T lymphocytes in allergic contact dermatitis suggests that it could be a potential target for the treatment of immune-related skin diseases.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.
authors.forename: Xingqi
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Xingxin
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle; D049109:Cell Proliferation; D003208:Concanavalin A; D016207:Cytokines / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000188:drug therapy*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010853:Picryl Chloride; D012269:Ribosomal Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D047630:Depsipeptides; D016328:NF-kappa B; D012269:Ribosomal Proteins; C488930:Rsp3a1 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D003208:Concanavalin A; C010324:roseotoxin B; D010853:Picryl Chloride