Article date: August 2010
By: D De Silva, MD Mitchell, JA Keelan in Volume 160, Issue 7, pages 1808-1822
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.
DOI: 10.1111/j.1476-5381.2010.00839.x
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