Received for publication November 9, 2007.
Revised March 28, 2008.
Accepted for publication March 28, 2008.

Histone deacetylase inhibitors exert time-dependent effects on Nuclear Factor-kappa B but consistently suppress the expression of labour-associated, pro-inflammatory genes in human myometrial cells

Abstract

Premature activation of the inflammatory processes that mediate human parturition leads to preterm birth, a major clinical problem associated with neonatal morbidity and mortality. Histone deacetylase inhibitors (HDACi) are currently in clinical trials for the treatment of inflammatory disorders. Recent evidence suggests that there may be a therapeutic use for HDACi in the management of preterm birth, with administration of HDACi to pregnant mice shown to delay delivery. Since NF-B is a key orchestrator of the inflammatory response and plays a pivotal role in parturition, it is important to understand how administration of HDACi might affect NF-B activity in human uterine tissues. We show here that the effects of HDACi on NF-B in human myometrial cells are time-dependent. Short-term exposure to HDACi enhanced IL-1-induced NF-B activity as a result of potentiating IKK activity, thereby leading to persistent turnover of IB/ proteins and prolonging NF-B phosphorylation, nuclear localisation and DNA binding. Conversely, long-term HDACi treatments resulted in repression of NF-B DNA binding. Nevertheless, both short- and long-term HDACi treatments inhibited the expression of four labour-associated pro-inflammatory genes (COX-2, IL-8, IL-6, RANTES), and this was associated with repression of the pro-inflammatory transcription factor c-Jun. Taken together, our data indicate that HDACi exert anti-inflammatory effects in human myometrium and may thus be useful in achieving a myometrial gene expression profile that favours uterine quiescence. However, co-administration of an IKK inhibitor may be both necessary and sufficient to circumvent potential induction of labour-associated pathways that could result from HDACi-induced augmentation of NF-B activity.

Key words: AP-1, NFkappaB, Regulation of gene expression, Cyclooxygenases