Inhibition of prolyl hydroxylase domain-containing protein suppressed lipopolysaccharide-induced TNF-α expression

Kotaro Takeda, Toshihiro Ichiki, Eriko Narabayashi, Keita Inanaga, Ryohei Miyazaki, Toru Hashimoto, Hirohide Matsuura, Jiro Ikeda, Toshio Miyata, Kenji Sunagawa

研究成果: ジャーナルへの寄稿学術誌査読

52 被引用数 (Scopus)

抄録

OBJECTIVE-: Prolyl hydroxylase domain-containing proteins (PHDs) play pivotal roles in oxygen-sensing system through the regulation of α-subunit of hypoxia-inducible factor (HIF), a key transcription factor governing a large set of gene expression to adapt hypoxia. Although tissue hypoxia plays an essential role in maintaining inflammation, the role of PHDs in the inflammatory responses has not been clearly determined. Here, we investigated the role of PHDs in lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF-α) induction in macrophages. METHODS AND RESULTS-: Northern blot analysis and ELISA revealed that LPS-induced TNF-α upregulation was strongly suppressed by PHD inhibitors, dimethyloxallyl glycine (DMOG), and TM6008 in RAW264.7 macrophages. DMOG suppressed LPS-induced TNF-α upregulation in HIF-1α-depleted cells and HIF-1α overexpression failed to suppress the induction of TNF-α. DMOG rather suppressed LPS-induced NF-κB transcriptional activity. Downregulation of Phd1 or Phd2 mRNA by RNA interference partially attenuated LPS-induced TNF-α induction. DMOG also inhibited LPS-induced TNF-α production in peritoneal macrophages as well as human macrophages. CONCLUSIONS-: PHD inhibition by DMOG or RNA interference inhibited LPS-induced TNF-α upregulation in macrophages possibly through NF-κB inhibition, which is independent of HIF-1α accumulation. This study suggests that PHDs are positive regulators of LPS-induced inflammatory process, and therefore inhibition of PHD may be a novel strategy for the treatment of inflammatory diseases.

本文言語英語
ページ(範囲)2132-2137
ページ数6
ジャーナルArteriosclerosis, thrombosis, and vascular biology
29
12
DOI
出版ステータス出版済み - 12月 2009

!!!All Science Journal Classification (ASJC) codes

  • 循環器および心血管医学

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