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

Abstract

TLR4/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. The 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. AO-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. AO-1 may reverse EOC cell-mediated immunosuppression through blocking TLR4/MD-2 complex-mediated MyD88/NF-κB signaling.

DOI: 10.1186/s12967-016-0845-5

Extracted Key Phrases

5 Figures and Tables

Cite this paper

@article{Liu2016AtractylenolideIM, title={Atractylenolide I modulates ovarian cancer cell-mediated immunosuppression by blocking MD-2/TLR4 complex-mediated MyD88/NF-κB signaling in vitro}, author={Hong Liu and Guonan Zhang and Jianming Huang and Shiqi Ma and Kun Mi and Jia Cheng and Yi Zhu and Xiao Wei Zha and Wei Huang}, journal={Journal of Translational Medicine}, year={2016}, volume={14}, pages={1-12} }