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Trypanocidal drug benznidazole impairs lipopolysaccharide induction of macrophage nitric oxide synthase gene transcription through inhibition of NF-kappaB activation.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2001 Sep 15; Vol. 167 (6), pp. 3422-6. - Publication Year :
- 2001
-
Abstract
- In murine macrophages, inducible NO synthase II (NOSII) gene expression is promoted at a transcriptional level by LPS and/or IFN-gamma with benznidazole (BZL), a trypanocidal drug, acting to down-regulate NOSII gene induction and hence inhibiting NO production. By performing transient transfection experiments, we now report that BZL also inhibited the expression of NOSII gene promoter or multimerized NF-kappaB binding site controlled reporter genes. By contrast, no effect was observed on the expression of a reporter gene under the control of the NOSII promoter-derived IFN regulatory factor element. EMSAs demonstrated that BZL inhibited the nuclear availability of NF-kappaB in stimulated macrophages. NF-kappaB is activated in macrophages by phosphorylation, ubiquitination, and subsequent proteolysis of IkappaB. Within this setting, Western blot was also performed to show that BZL blocked IkappaBalpha degradation. Collectively, these results demonstrate that BZL is able to specifically inhibit macrophage NF-kappaB activation after LPS plus IFN-gamma stimulation.
- Subjects :
- Animals
Blotting, Western
Cells, Cultured drug effects
Cells, Cultured enzymology
Depression, Chemical
Enzyme Induction drug effects
Genes, Reporter
I-kappa B Proteins metabolism
Interferon-gamma pharmacology
Isoenzymes genetics
Macrophages enzymology
Mice
NF-kappa B metabolism
Nitric Oxide Synthase genetics
Nitric Oxide Synthase Type II
Nitrites metabolism
Phosphorylation
Protein Processing, Post-Translational
Recombinant Fusion Proteins biosynthesis
Transfection
Ubiquitin metabolism
Isoenzymes biosynthesis
Lipopolysaccharides pharmacology
Macrophages drug effects
NF-kappa B antagonists & inhibitors
Nitric Oxide Synthase biosynthesis
Nitroimidazoles pharmacology
Transcription, Genetic drug effects
Trypanocidal Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 167
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 11544334
- Full Text :
- https://doi.org/10.4049/jimmunol.167.6.3422