論文

査読有り
2016年3月

Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment

ONCOGENE
  • A. Deguchi
  • ,
  • T. Tomita
  • ,
  • U. Ohto
  • ,
  • K. Takemura
  • ,
  • A. Kitao
  • ,
  • S. Akashi-Takamura
  • ,
  • K. Miyake
  • ,
  • Y. Maru

35
11
開始ページ
1445
終了ページ
1456
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/onc.2015.211
出版者・発行元
NATURE PUBLISHING GROUP

S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-kappa B in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.

Web of Science ® 被引用回数 : 21

リンク情報
DOI
https://doi.org/10.1038/onc.2015.211
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/26165843
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000372196400010&DestApp=WOS_CPL

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