Atractylenolide I modulates ovarian cancer cell-mediated immunosuppression by blocking MD-2/TLR4 complex-mediated MyD88/NF-κB signaling in vitro

Journal of Translational Medicine

Research

Jia Cheng¹  Xiao Zha¹  Kun Mi¹  Shiqi Ma¹  Jianming Huang¹  Guonan Zhang²  Yi Zhu³  Wei Huang⁴  Hong Liu⁵ 

[1] Department of Biochemistry and Molecular Biology, Sichuan Cancer Institute, No.55, Section 4 of South People’s Road, 610041, Chengdu, China;Department of Gynecologic Oncology, Sichuan Cancer Hospital, No.55, Section 4 of South People’s Road, 610041, Chengdu, China;Department of Gynecologic Oncology, Sichuan Cancer Hospital, No.55, Section 4 of South People’s Road, 610041, Chengdu, China;Department of Ultrasound, Sichuan Cancer Hospital, No.55, Section 4 of South People’s Road, 610041, Chengdu, China;Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, No. 20, Section 3 of South People’s Road, 610041, Chengdu, China;Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, No. 20, Section 3 of South People’s Road, 610041, Chengdu, China;Department of Gynecologic Oncology, Sichuan Cancer Hospital, No.55, Section 4 of South People’s Road, 610041, Chengdu, China;

关键词: Epithelial ovarian cancer;    TLR4/MD-2 complex;    MyD88/NF-κB signaling;    Atractylenolide I;    Immunosuppressive cytokines;    Indoleamine 2,3-dioxygenase;   

DOI  :  10.1186/s12967-016-0845-5

 received in 2015-10-15, accepted in 2016-03-30,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundTLR4/MD-2 complex-mediated MyD88-dependent activation of NF-κB and Akt promotes tumor-associated immunosuppression in epithelial ovarian cancer (EOC) via induction of immunesuppressive cytokines and indoleamine 2,3-dioxygenase (IDO). Atractylenolide I (AO-1) is a naturally occurring sesquiterpene lactone known to change the conformational ensemble of human MD-2 on EOC cells. This study examined the modulation by AO-1 of TLR4/MD-2 complex-mediated MyD88/NF-κB signaling.MethodsThe expression and activation of NF-κB, Akt and IDO1 by MyD88+ EOC SKOV3 cells was determined using western blot; the TLR4/MD-2 complex on SKOV3 cells and the phenotype of T lymphocytes were determined using flow cytometry; IDO activity was evaluated by measuring l-kynurenine; Immunesuppressive cytokines were detected using ELISA; T‐cell proliferation to mitogen stimulation was assessed by MTT assay; the cytotoxicity of lymphocytes and NK cells was measured using LDH-cytotoxicity assay.ResultsAO-1 could down-regulate expression of TLR4/MD-2 complex, resulting in downregulation of MyD88/NF-κB signaling and activation of NF-κB, Akt and IDO1 and secretion of IL-6, TGF-β1, VEGF and IL-17A by EOC SKOV3 cells, and further reduce increased levels of regulatory T cells (Treg cells) and improve decreased proliferative response and antitumor cytotoxicity of T lymphocytes exposed to EOC SKOV3 cell supernatant.ConclusionAO-1 may reverse EOC cell-mediated immunosuppression through blocking TLR4/MD-2 complex-mediated MyD88/NF-κB signaling.

【 授权许可】

CC BY   
© Liu et al. 2016

【 图 表 】

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