Histone Deacetylase Inhibitors Exert Time-Dependent Effects on Nuclear Factor-κB but Consistently Suppress the Expression of Proinflammatory 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. 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)-1␤-induced NF-B activity as a result of potentiating IB kinase (IKK)␤ activity, thereby leading to persistent turnover of IB␣/ proteins and prolonging NF-B phosphorylation, nuclear localization, and DNA binding. Conversely, longterm 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 IKK␤ 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.During parturition, myometrium undergoes a transition from a state of quiescence to one of contractility, resulting in delivery of the neonate. Although the molecular mechanisms that underpin this transition are poorly understood, it is widely accepted that parturition is an inflammatory process, involving the up-regulation of multiple proinflammatory genes (Romero et al., 2006). Premature activation of uterine proinflammatory pathways can lead to preterm birth, a major clinical problem that occurs in 5 to 10% of pregnancies and is associated with 70 to 75% of neonatal morbidity/ mortality (Wen et al., 2004).Histone acetylation plays a major role in gene transcription, enabling the partial unraveling of local chromatin structure that is required to make the DNA accessible for binding by transcription factors and the basal transcription machinery (Li et al., 2004). Acetylation is reversible and reflects a dynamic balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Aberrant recruitment of HDACs to promoters and/or overexpression of HDACs are observed in cancer cells, and This work was supported by Tommy's Campaign. Article, publication date, and citation information can be foun...

Intermittent and sustained hypoxia induce a similar gene expression profile in human aortic endothelial cells

“…Our results stand in stark contrast to those of Ryan et al (56), where IH, but not SH, induced NF-B-regulated genes and increased NF-B DNA binding activity in HeLa cells. In our study, both stimuli induced the NF-B pathway, including NF-B-regulated HSP90 (3), TNFSF4 (22), and CXCR4 (25) and upregulated NF-B activator histone deacetylase (36). IL-8 was the only NF-B-regulated gene, which was differentially expressed in the two conditions, but the difference was no longer present at the protein level.…”

Class I to III Histone Deacetylases Differentially Regulate Inflammation-Induced Matrix Metalloproteinase 9 Expression in Primary Amnion Cells

“…However, the paradoxical inhibitory effects of HDACi on gene expression observed in this study and others 16,18,36,[39][40][41][42] suggest that other components of the transcriptional response, in addition to histones, are regulated by acetylation. In support, a number of nonhistone proteins have been identified as targets for HDACi including nuclear factor kB (NF-kB).…”

“…We thus hypothesize that the actions of TSA and SAHA may be attributed to their inhibitory actions on class II HDAC. There are a few studies on gestational tissues, which show a major effect of TSA and SAHA in repressing the production of proinflammatory cytokines, 16,36 COX-2, and resultant prostaglandin production. 16,18 There have been no studies that have specifically assessed the antiinflammatory effects of specific class I or II inhibitors of HDAC in human fetal membranes or myometrium.…”

“…There are a few studies on gestational tissues, which show a major effect of TSA and SAHA in repressing the production of proinflammatory cytokines, 16,36 COX-2, and resultant prostaglandin production. 16,18 There have been no studies that have specifically assessed the antiinflammatory effects of specific class I or II inhibitors of HDAC in human fetal membranes or myometrium. However, the class I-specific HDACi suberic bishydroxamate has been shown to exert potent inhibitory effects on human uterine contractions; similar results were obtained using TSA and SAHA.…”

“…[16][17][18] In addition, our own studies on SIRT1 and SIRT6 also reveal a functional role in regulating proinflammatory cytokines in fetal membranes. 19,20 However, whether class I and class II HDACs and the class III HDAC SIRT1 also regulate MMP-9 expression and activity in human fetal membranes is not known.…”