Abstract | OBJECTIVE: METHODS AND RESULTS: Northern blot analysis and ELISA revealed that LPS-induced TNF-alpha upregulation was strongly suppressed by PHD inhibitors, dimethyloxallyl glycine (DMOG), and TM6008 in RAW264.7 macrophages. DMOG suppressed LPS-induced TNF-alpha upregulation in HIF-1alpha-depleted cells and HIF-1alpha overexpression failed to suppress the induction of TNF-alpha. DMOG rather suppressed LPS-induced NF-kappaB transcriptional activity. Downregulation of Phd1 or Phd2 mRNA by RNA interference partially attenuated LPS-induced TNF-alpha induction. DMOG also inhibited LPS-induced TNF-alpha production in peritoneal macrophages as well as human macrophages. CONCLUSIONS: PHD inhibition by DMOG or RNA interference inhibited LPS-induced TNF-alpha upregulation in macrophages possibly through NF-kappaB inhibition, which is independent of HIF-1alpha 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.
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Authors | Kotaro Takeda, Toshihiro Ichiki, Eriko Narabayashi, Keita Inanaga, Ryohei Miyazaki, Toru Hashimoto, Hirohide Matsuura, Jiro Ikeda, Toshio Miyata, Kenji Sunagawa |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 29
Issue 12
Pg. 2132-7
(Dec 2009)
ISSN: 1524-4636 [Electronic] United States |
PMID | 19762779
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amino Acids, Dicarboxylic
- Cytokines
- Enzyme Inhibitors
- HIF1A protein, human
- Hif1a protein, mouse
- Hypoxia-Inducible Factor 1, alpha Subunit
- Lipopolysaccharides
- NF-kappa B
- Tumor Necrosis Factor-alpha
- PHD1 protein, mouse
- Procollagen-Proline Dioxygenase
- Egln1 protein, mouse
- Hypoxia-Inducible Factor-Proline Dioxygenases
- oxalylglycine
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Topics |
- Amino Acids, Dicarboxylic
(pharmacology)
- Animals
- Cell Line
- Cytokines
(biosynthesis)
- Enzyme Inhibitors
(pharmacology)
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(genetics, metabolism)
- Hypoxia-Inducible Factor-Proline Dioxygenases
- Lipopolysaccharides
(toxicity)
- Macrophages
(drug effects, metabolism)
- Macrophages, Peritoneal
(drug effects, metabolism)
- Mice
- NF-kappa B
(genetics, metabolism)
- Procollagen-Proline Dioxygenase
(antagonists & inhibitors, genetics)
- RNA Interference
- Transcriptional Activation
- Tumor Necrosis Factor-alpha
(biosynthesis)
- Up-Regulation
(drug effects)
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