Abstract
Metformin, an antidiabetic agent, has been shown to reduce atherothrombotic disease in diabetic patients independent of antihyperglycemic effect. Recent studies have demonstrated that metformin attenuates the proinflammatory responses in human vascular wall cells and macrophages. However, the detailed molecular mechanisms underlying these therapeutic effects remain unclear. In the present study, we investigated the effects of metformin on tumor necrosis factor (TNF) production and tissue factor (TF) expression in isolated human monocytes stimulated with lipopolysaccharide (LPS) or oxidized low-density lipoprotein (oxLDL). Metformin significantly inhibited both TNF production and TF expression in isolated human monocytes stimulated with LPS or oxLDL. Metformin also significantly inhibited TNF and TF mRNA in human monocytes stimulated with LPS. Although metformin did not inhibit the activation of either nuclear factor-κB or activator protein-1, it inhibited the expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 in monocytes stimulated with LPS or oxLDL. These results suggest that metformin may attenuate the inflammatory responses, at least in part, by suppressing the production of both TNF and TF through the inhibition of the ERK1/2-Egr-1 pathway in human monocytes.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.164970.
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ABBREVIATIONS:
- TNF
- tumor necrosis factor
- AMPK
- AMP-activated protein kinase
- AP-1
- activator protein-1
- Egr-1
- early growth response factor-1
- ELISA
- enzyme-linked immunosorbent assay
- ERK
- extracellular signal-regulated protein kinase
- JNK
- c-Jun N-terminal kinase
- LPS
- lipopolysaccharide
- NF-κB
- nuclear factor-κB
- oxLDL
- oxidized low-density lipoprotein
- TF
- tissue factor
- RT-PCR
- reverse transcription-polymerase chain reaction
- IκΒ
- inhibitor κB.
- Received December 24, 2009.
- Accepted March 31, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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