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Histone Deacetylase Inhibitors Exert Time-Dependent Effects on Nuclear Factor-B but Consistently Suppress the Expression of Proinflammatory Genes in Human Myometrial Cells

Department of Reproductive Biology, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom (T.M.L., A.R.M., P.R.B.); and Department of Maternal and Fetal Medicine, Chelsea and Westminster Hospital, Imperial College London, London, United Kingdom (M.R.J.)

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. Because 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 nuclear factor-B (NF-B) in human myometrial cells are time-dependent. Short-term exposure to HDACi enhanced interleukin (IL)-1β-induced NF-B activity as a result of potentiating IB kinase (IKK)β activity, thereby leading to persistent turnover of IB/ proteins and prolonging NF-B phosphorylation, nuclear localization, 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 labor-associated proinflammatory genes (COX-2, IL-8, IL-6, and RANTES), and this was associated with repression of the proinflammatory transcription factor c-Jun. 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 favors uterine quiescence. However, coadministration of an IKKβ inhibitor may be both necessary and sufficient to circumvent potential induction of labor-associated pathways that could result from HDACi-induced augmentation of NF-B activity.

Address correspondence to: Dr. Tamsin M Lindström, 3rd Floor IRDB, Imperial College London, Hammersmith Campus, Du Cane Rd., London W12 0NN, UK. E-mail: tamsinlindstrom{at}gmail.com