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• W2096003375 abstract "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-κB1 (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" @default.
• W2096003375 created "2016-06-24" @default.
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• W2096003375 date "2001-05-01" @default.
• W2096003375 modified "2023-10-13" @default.
• W2096003375 title "The biphasic immunoregulation of pyrimidylpiperazine (Y-40138) is IL-10 sensitive and requires NF-κB targeting in the alveolar epithelium" @default.
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• W2096003375 doi "https://doi.org/10.1038/sj.bjp.0704041" @default.
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