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

作者：Liu, Hong; Zhang, Guonan; Huang, Jianming; Ma, Shiqi; Mi, Kun; Cheng, Jia; Zhu, Yi; Zha, Xiao; Huang, Wei^*

来源：Journal of Translational Medicine, 2016, 14(1): 104.

DOI：10.1186/s12967-016-0845-5

• Epithelial ovarian cancer
• TLR4/MD-2 complex
• MyD88/NF-kappa B signaling
• Atractylenolide I
• Immunosuppressive cytokines
• Indoleamine 2,3-dioxygenase

Background: TLR4/MD-2 complex-mediated MyD88-dependent activation of NF-kappa B 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-kappa B signaling.
Methods: The expression and activation of NF-kappa B, 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.
Results: AO-1 could down-regulate expression of TLR4/MD-2 complex, resulting in downregulation of MyD88/NF-kappa B signaling and activation of NF-kappa B, Akt and IDO1 and secretion of IL-6, TGF-beta 1, 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.
Conclusion: AO-1 may reverse EOC cell-mediated immunosuppression through blocking TLR4/MD-2 complex-mediated MyD88/NF-kappa B signaling.

• 出版日期2016-4-27
• 单位四川大学; 四川省肿瘤医院