Inhibition of choriodecidual cytokine production and inflammatory gene expression by selective I-kappaB kinase (IKK) inhibitors.
OBJECTIVE
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.


METHODS
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.


RESULTS
Two IKKbeta 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
These studies provide evidence that pharmacological inhibition of IKKbeta 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.
De Silva
D
D
Liggins Institute, University of Auckland, Auckland, New Zealand.
Mitchell
M D
MD
Keelan
J A
JA
D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D003656:Decidua / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D015151:Immunoblotting; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D051550:I-kappa B Kinase