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The biphasic immunoregulation of pyrimidylpiperazine (Y-40138) is IL-10 sensitive and requires NF-kappa B targeting in the alveolar epithelium.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2001 May; Vol. 133 (1), pp. 49-60. - Publication Year :
- 2001
-
Abstract
- 1. Pyrimidylpiperazine (Y-40138), a synthetic derivative of N-[1-(4-([4-(pyrimidin-2-yl)piperazin-1-yl]methyl)phenyl)cyclopropyl] acetamide, is a novel dual regulator of pro- and anti-inflammatory cytokines in vivo. The aim of the present study was to determine the signal transduction mechanisms implicated in vitro. 2. In alveolar epithelial cells, pre-treatment (30 min) with Y-40138 reduced LPS-induced biosynthesis of IL-1 beta, IL-6 and TNF-alpha, an effect paralleled by up-regulating an anti-inflammatory counter-loop mediated through IL-10. 3. This differential regulation of pro- and anti-inflammatory signals was accompanied by an inhibition of the nuclear localization of selective NF-kappa B subunits, particularly NF-kappa B(1) (p50), RelA (p65), the major transactivating member of the Rel family, RelB (p68) and c-Rel (p75). In addition, Y-40138 blockaded, in a dose-dependent manner, the LPS-induced nuclear activation of NF-kappa B. 4. Analysis of the upstream pathway involved in Y-40138-dependent retardation of LPS-induced NF-kappa B translocation/activation revealed the involvement of an I kappa B-alpha sensitive pathway. Pre-treatment with Y-40138 ameliorated LPS-induced degradation of I kappa B-alpha in the cytosolic compartment and retarded its phosphorylation, suggesting the involvement of an upstream kinase. 5. Recombinant IL-10 (0 -- 10 ng ml(-1)) blockaded, in a dose-dependent manner, LPS-induced biosynthesis of IL-1 beta, IL-6 and TNF-alpha. Furthermore, rhIL-10 reduced the DNA binding activity of NF-kappa B. Immunoneutralization of endogenous IL-10 by a polyclonal alpha IL-10 (5 microg ml(-1)) reversed the inhibitory effect of Y-40138 on pro-inflammatory cytokines and partially restored the DNA binding activity of NF-kappa B. 6. These results indicate that Y-40138 mediated dual immunoregulation of pro- and anti-inflammatory cytokines is IL-10 sensitive and mediated through the I kappa B-alpha/NF-kappa B signal transduction pathway.
- Subjects :
- Acetamides immunology
Active Transport, Cell Nucleus drug effects
Animals
Blotting, Western
Cells, Cultured
Cytokines biosynthesis
Cytokines metabolism
DNA metabolism
DNA-Binding Proteins metabolism
Electrophoresis, Polyacrylamide Gel
Enzyme-Linked Immunosorbent Assay
Epithelial Cells metabolism
Immune Sera immunology
Inhibitory Concentration 50
Interleukin-10 immunology
Lipopolysaccharides antagonists & inhibitors
Lipopolysaccharides pharmacology
Lung cytology
Lung metabolism
Models, Biological
NF-KappaB Inhibitor alpha
NF-kappa B antagonists & inhibitors
NF-kappa B chemistry
Phosphorylation drug effects
Piperazines immunology
Protein Binding drug effects
Protein Processing, Post-Translational drug effects
Protein Subunits
Rats
Signal Transduction drug effects
Acetamides pharmacology
Epithelial Cells drug effects
I-kappa B Proteins
Interleukin-10 pharmacology
Lung drug effects
NF-kappa B metabolism
Piperazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 133
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 11325794
- Full Text :
- https://doi.org/10.1038/sj.bjp.0704041