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. Because NF-κB 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-κB activity in human uterine tissues. We show here that the effects of HDACi on nuclear factor-κB (NF-κB) in human myometrial cells are time-dependent. Short-term exposure to HDACi enhanced interleukin (IL)-1β-induced NF-κB activity as a result of potentiating IκB kinase (IKK)β activity, thereby leading to persistent turnover of IκBα/ϵ proteins and prolonging NF-κB phosphorylation, nuclear localization, and DNA binding. Conversely, long-term HDACi treatments resulted in repression of NF-κB 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-κB activity.
Footnotes
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This work was supported by Tommy's Campaign.
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ABBREVIATIONS: HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor(s); NF-κB, nuclear factor-κB; SIRT, Sirtuin; IκB, inhibitor of κB; IKK, inhibitor of κB kinase; SCFβ-TrCP, ligase composed of Skp1, Cdc53/Cu11, and a specificity-conferring F-box protein, in this case β-transducin repeat-containing protein (βTrCP); COX, cyclooxygenase-2; TSA, trichostatin A; IL, interleukin; SAHA, suberoylanilide hydroxamic acid; PBS, phosphate-buffered saline; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; EMSA, electrophoretic mobility shift assay; LUC, luciferase; PCR, polymerase chain reaction; RANTES, regulated on activation normal T cell expressed and secreted; ac-HH4, acetylated histone H4; CRM, chromosome maintenance.
- Received November 9, 2007.
- Accepted March 28, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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