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The biphasic immunoregulation of pyrimidylpiperazine (Y‐40138) is IL‐10 sensitive and requires NF‐κB targeting in the alveolar epithelium
Author(s) -
Haddad J J E,
SafiehGarabedian B,
Saadé N E,
Land S C
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704041
Subject(s) - relb , iκbα , nf κb , microbiology and biotechnology , signal transduction , p50 , chemistry , endogeny , cytosol , phosphorylation , in vivo , in vitro , kinase , nfkb1 , biology , biochemistry , transcription factor , enzyme , gene
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 . In alveolar epithelial cells, pre‐treatment (30 min) with Y‐40138 reduced LPS‐induced biosynthesis of IL‐1β, IL‐6 and TNF‐α, an effect paralleled by up‐regulating an anti‐inflammatory counter‐loop mediated through IL‐10. This differential regulation of pro‐ and anti‐inflammatory signals was accompanied by an inhibition of the nuclear localization of selective NF‐κB subunits, particularly NF‐κB 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‐κB. Analysis of the upstream pathway involved in Y‐40138‐dependent retardation of LPS‐induced NF‐κB translocation/activation revealed the involvement of an IκB‐α sensitive pathway. Pre‐treatment with Y‐40138 ameliorated LPS‐induced degradation of IκB‐α in the cytosolic compartment and retarded its phosphorylation, suggesting the involvement of an upstream kinase. Recombinant IL‐10 (0 – 10 ng ml −1 ) blockaded, in a dose‐dependent manner, LPS‐induced biosynthesis of IL‐1β, IL‐6 and TNF‐α. Furthermore, rhIL‐10 reduced the DNA binding activity of NF‐κB. Immunoneutralization of endogenous IL‐10 by a polyclonal αIL‐10 (5 μg ml −1 ) reversed the inhibitory effect of Y‐40138 on pro‐inflammatory cytokines and partially restored the DNA binding activity of NF‐κB. These results indicate that Y‐40138 mediated dual immunoregulation of pro‐ and anti‐inflammatory cytokines is IL‐10 sensitive and mediated through the IκB‐α/NF‐κB signal transduction pathway.British Journal of Pharmacology (2001) 133 , 49–60; doi: 10.1038/sj.bjp.0704041