Aspirin Inhibits Tumor Necrosis Factor-α Gene Expression in Murine Tissue Macrophages
Abstract
Aspirin has been reported to inhibit the activation of nuclear factor-κB (NF-κB) through stabilization of inhibitor κB (IκB). This observation led us to investigate the role of aspirin in suppressing the activation of the NF-κB-regulated tumor necrosis factor-α (TNF-α) gene expression in primary macrophages. We now report that therapeutic doses of aspirin suppress lipopolysaccharide-inducible NF-κB binding to an NF-κB binding site in the TNF-α promoter, lipopolysaccharide-induced TNF-α mRNA accumulation, and protein secretion. IκB is also stabilized under these conditions. The aspirin-initiated stabilization of IκB, suppression of induced TNF-α mRNA, and NF-κB binding to the TNF-α promoter are blocked by pretreatment with pertussis toxin. These studies suggest that aspirin may exert significant anti-inflammatory effects by suppressing the production of macrophage-derived inflammatory mediators.
Footnotes
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Send reprint requests to: Salvatore V. Pizzo, M.D., Ph.D., Department of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710. E-mail: pizzo0001{at}mc.duke.edu
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This work was supported by Research Grants HL-24066 and CA-29589.
- Abbreviations:
- NF-κB
- nuclear factor-κB
- IκB
- inhibitor κB
- TNF-α
- tumor necrosis factor-α
- LPS
- lipopolysaccharide
- EMSA
- electrophoretic mobility shift assay
- DTT
- dithiothreitol
- MTT
- 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, RPMI, Roswell Park Memorial Institute
- ELISA
- enzyme-linked immunosorbent assay
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- Received May 6, 1997.
- Accepted May 29, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
