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Inhibition of choriodecidual cytokine production and inflammatory gene expression by selective I‐κB kinase (IKK) inhibitors
Author(s) -
De Silva D,
Mitchell MD,
Keelan JA
Publication year - 2010
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 - 10.1111/j.1476-5381.2010.00839.x
Subject(s) - parthenolide , pharmacology , cytokine , iκb kinase , tumor necrosis factor alpha , inflammation , apoptosis , gene expression , iκbα , signal transduction , chemistry , nf κb , cancer research , biology , immunology , biochemistry , gene
BACKGROUND AND PURPOSE Inflammation of the extraplacental membranes plays a key role in the pathogenesis of preterm labour. The aim of this study was to screen a number of commercially available small molecule nuclear factor‐kappa B inhibitors to identify candidates suitable for clinical evaluation as anti‐inflammatory agents for the prevention of preterm birth. EXPERIMENTAL APPROACH Nine inhibitors were evaluated across a range of concentrations for their ability to inhibit lipopolysaccharide (LPS)‐stimulated cytokine production in primary term choriodecidual cells in culture without affecting cell viability. Expression of 112 inflammation‐ and apoptosis‐related genes was evaluated using boutique oligonucleotide arrays. KEY RESULTS Two IKKβ inhibitors were found to be highly effective and non‐toxic inhibitors of choriodecidual cytokine production: parthenolide and [5‐(p‐fluorophenyl)‐2‐ureido] thiophene‐3‐carboxamide (TPCA‐1). Both compounds also inhibited LPS‐stimulated nuclear translocation of p65/RelA. Expression of 38 genes on the arrays (34%) was significantly ( P < 0.05) inhibited by TPCA‐1 or parthenolide. Of the 14 genes significantly stimulated by LPS, all were inhibited by TPCA‐1 and 12 were inhibited by parthenolide. Overall, gene expression was more robustly inhibited by TPCA‐1 than parthenolide; however, expression of two genes was only inhibited by parthenolide. Neither compound significantly altered the expression profile of anti‐apoptosis genes on the arrays. CONCLUSIONS AND IMPLICATIONS These studies provide evidence that pharmacological inhibition of IKKβ activity holds promise as a potential strategy for the prevention and/or treatment of inflammation‐driven preterm birth. TPCA‐1 appeared the most promising compound among those tested in this study. Different inhibitors may have subtly different effect profiles despite having similar modes of action.