期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 160, 期 7, 页码 1808-1822出版社
WILEY
DOI: 10.1111/j.1476-5381.2010.00839.x
关键词
inflammation; lipopolysaccharide; NF-kappa B; I-kappa B kinase; choriodecidua; gene expression; preterm labour
资金
- March of Dimes Foundation [21-FY05-1247]
- Maurice and Phyllis Paykel Trust
- University of Auckland
- Women and Infants Research Foundation (WA)
- Royal Society of New Zealand
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 IKK beta 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 IKK beta 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.
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