Hypoxia diminishes toll-like receptor 4 expression through reactive oxygen species generated by mitochondria in endothelial cells

Itaru Ishida, Hiroshi Kubo, Satoshi Suzuki, Tomoko Suzuki, Sachiko Akashi, Kunihiko Inoue, Sumiko Maeda, Hideaki Kikuchi, Hidetada Sasaki, Takashi Kondo

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Hypoxia and inflammation often occur simultaneously due to prevention of adequate gas exchange. Understanding the influence of hypoxia on the inflammatory response is important because hypoxia directly regulates expression of many genes, including those regulating inflammation, and plays a role in modulating the resolution of an inflammatory response. LPS is a major mediator of cellular injury and inflammation that induces its effects through Toll-like receptor 4 (TLR4). The aim of this study was to evaluate the effect of hypoxia on TLR4 expression. Hypoxia decreased TLR4 expression on cultured endothelial cells. Furthermore, LPS-induced ICAM-1 up-regulation was decreased by hypoxia. Because reactive oxygen species (ROS) generated from mitochondria are one of the signaling molecules induced by hypoxia, the role of ROS in hypoxia-induced TLR4 down-regulation was evaluated. Our data showed that hypoxia increased ROS generation and that hypoxia-induced TLR4 down-regulation was inhibited by myxothiazol, a mitochondrial site III electron transport inhibitor. Hypoxia also inhibited AP-1 translocation. Since the TLR4 promoter has a binding site for AP-1, hypoxia-induced TLR4 down-regulation may be due to an ROS-mediated decrease in AP-1-binding activity. We conclude that hypoxia decreases TLR4 expression in endothelial cells and that this change is mediated by mitochondrial ROS leading to attenuation of AP-1 transcriptional activity.

Original languageEnglish
Pages (from-to)2069-2075
Number of pages7
JournalJournal of Immunology
Volume169
Issue number4
DOIs
Publication statusPublished - 2002 Aug 15
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Ishida, I., Kubo, H., Suzuki, S., Suzuki, T., Akashi, S., Inoue, K., Maeda, S., Kikuchi, H., Sasaki, H., & Kondo, T. (2002). Hypoxia diminishes toll-like receptor 4 expression through reactive oxygen species generated by mitochondria in endothelial cells. Journal of Immunology, 169(4), 2069-2075. https://doi.org/10.4049/jimmunol.169.4.2069