Inhibition of choriodecidual cytokine production and inflammatory gene expression by selective I-kappa B kinase (IKK) inhibitors

De Silva, D., Mitchell, M. D. and Keelan, J. A. (2010) Inhibition of choriodecidual cytokine production and inflammatory gene expression by selective I-kappa B kinase (IKK) inhibitors. British Journal of Pharmacology, 160 7: 1808-1822. doi:10.1111/j.1476-5381.2010.00839.x

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Author De Silva, D.
Mitchell, M. D.
Keelan, J. A.
Title Inhibition of choriodecidual cytokine production and inflammatory gene expression by selective I-kappa B kinase (IKK) inhibitors
Formatted title
Inhibition of choriodecidual cytokine production and inflammatory gene expression by selective I-κB kinase (IKK) inhibitors
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
Publication date 2010-08
Sub-type Article (original research)
DOI 10.1111/j.1476-5381.2010.00839.x
Volume 160
Issue 7
Start page 1808
End page 1822
Total pages 15
Place of publication West Sussex, United Kingdom
Publisher John Wiley & Sons
Collection year 2011
Language eng
Subject 0604 Genetics
1103 Clinical Sciences
Formatted abstract
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 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 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. © 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society.
Keyword inflammation
lipopolysaccharide
NF-kappa B
I-kappa B kinase
choriodecidua
gene expression
preterm labour
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2011 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 18 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 26 Aug 2010, 12:50:21 EST