title: Neochromine S5 improves contact hypersensitivity through a selective effect on activated T lymphocytes.
abstract: Strategy on activated T cells is an effective treatment for T cell mediated diseases. By using a synthesized chromone derivative, we examined its effects on the activated T cells. This compound, (Z)-1,3-dihydroxy-9-methyl-13H-benzo[b]chromeno[3,2-f][1,4]oxazepin-13-one (neochromine S5), exhibited immunosuppressive activity in vitro and in vivo. Interestingly, neochromine S5 selectively inhibited proliferation and induced apoptosis in T lymphocytes activated by concanavalin A (Con A) in a dose-dependent manner but not in naïve T lymphocytes, distinct from quercetin. This compound triggered mitochondrial apoptotic pathway including cleavage of caspase 3, caspase 9 and PARP, downregulation of bcl-2 and release of cytochrome c in activated T cells, but did not affect ER stress or Fas signals. In addition, neochromine S5 downregulated the expression of CD25 and CD69 and the production of inflammatory cytokines, including TNFα, IFNγ and IL-2, improved ear swelling in mice with contact hypersensitivity, reduced CD4(+) T cells infiltration, and increased apoptosis of isolated T lymphocytes from peripheral lymph nodes. Moreover, neochromine S5 showed no effect on the weight of mice and their immune organs, while dexamethasone caused a significant weight loss. Taken together, our results suggest that neochromine S5 exerts a unique anti-inflammatory activity mainly through a selective effect on activated T cells, which is different from the current immunosuppressant, dexamethasone.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: State Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Electronic address: sunyangnju@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Electronic address: xudongwu@nju.edu.cn.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D002867:Chromones
keywords: Activated T lymphocytes; Contact hypersensitivity; Mitochondrial apoptosis; Neochromine S5