title: Trichomide A, a natural cyclodepsipeptide, exerts immunosuppressive activity against activated T lymphocytes by upregulating SHP2 activation to overcome contact dermatitis.
abstract: Increasing numbers of people are suffering from allergic contact dermatitis. However, the immunosuppressive drug candidate with negligible toxicity is still deficient. In the present study, we identified a natural cyclodepsipeptide named trichomide A that effectively inhibited the proliferation of activated T cells and reduced the production of proinflammatory cytokines but had almost no toxic effect on naive T cells at 0.3-3 μM. In addition, trichomide A caused G0/G1 phase arrest, suppressed the activation of AKT and STAT3, and increased the level of phosphorylated SHP2 in activated T cells in dose- and time-dependent manners. Furthermore, an in vivo experiment demonstrated that trichomide A significantly ameliorated picryl chloride (PCI)-induced contact hypersensitivity in mice. Such effects of trichomide A in the aforementioned experiments were significantly reversed by the inhibition of SHP2 activity using the SHP2-specific inhibitor PHPS1 or conditional SHP2 knockout mice in T cells, suggesting the SHP2-dependent action of trichomide A. Taken together, trichomide A showed an immunosuppressive activity against T cell-mediated immune responses both in vitro and in vivo, which has potential for the treatment of immune-related skin diseases.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 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: 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: Jian
authors.initials: J
authors.lastname: Gao
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: 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: 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: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Laboratory of Cell Signaling and Modeling Genetics, Institute of Molecular Pathology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: rxtan@nju.edu.cn.
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. Electronic address: yangsun@nju.edu.cn.
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; D002453:Cell Cycle; D049109:Cell Proliferation; D047630:Depsipeptides / Q000494:pharmacology*; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D012871:Skin Diseases / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D014443:Tyrosine / Q000737:chemistry
chemical_list: D047630:Depsipeptides; D007166:Immunosuppressive Agents; C000590734:trichomide A; D014443:Tyrosine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11