Abstract
E2 attenuates inflammatory responses by suppressing expression of pro-inflammatory genes. Given that inflammation is increasingly being associated with neurodegenerative and psychiatric processes, we sought to elucidate mechanisms by which E2 down-regulates a component of an inflammatory response, cyclooxygenase– 2 (COX-2) expression. Although inflammatory processes in the brain are usually associated with microglia and astrocytes, we found that the COX-2 gene (cox-2) was expressed in a neuronal context, specifically in an amygdalar cell line (AR-5). Given that COX-2 has been reported to be in neurons in the brain, and that the amygdala is a site involved in neurodegenerative and neuropsychiatric processes, we investigated mechanisms by which E2 could down-regulate cox-2 expression in the AR-5 line. These cells express estrogen receptors alpha (ERα) and beta (ERβ), and as shown here cox-2. At the level of RNA, E2 and the ERβ selective ligand diarylpropionitrile (DPN) both attenuated gene expression, whereas the ERα selective ligand propyl pyrazole triol (PPT) had no effect. Neither ligand increased ERβ at the cox-2 promoter. Rather, DPN decreased promoter occupancy of NF-κB p65 and histone 4 (H4) acetylation. Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the TSA effect, E2 and DPN increased histone deacetylase one (HDAC1) and switch-independent 3A (Sin3A) promoter occupancy. Lastly, even though E2 increased CpG methylation, DPN did not. Taken together, the pharmacological data indicate that ERβ contributes to neuronal cox-2 expression, as measured by RNA levels. Furthermore, ER ligands lead to increased recruitment of HDAC1, Sin3A and a concomitant reduction of p65 occupancy and Ac-H4 levels. None of the events, however, are associated with a significant recruitment of ERβ at the promoter. Thus, ERβ directs recruitment to the cox-2 promoter, but does so in the absence of being recruited itself.
Highlights
A kinetic analysis revealed no differences between E2, DPN and propyl pyrazole triol (PPT) induced changes in mRNA levels until 24 hrs
To our knowledge no studies have addressed whether E2 suppresses cox-2 expression in neurons
The E2 effect on both RNA levels is mediated by ERβ but not ERα, in so far as PPT has no effect on cyclooxygenase– 2 (COX-2) mRNA and hnRNA levels
Summary
17β-estradiol (E2) is a steroid hormone whose functions far exceed regulation of female reproductive functions [1,2]. Studies of human postmortem brain indicate that in Alzheimer’s disease (AD), there is increased COX-2 immunostaining in a subset of neurons of the hippocampus [21]. Target genes include the cytokine-induced neutrophil chemoattractant (CINC)-2β, monocyte chemotactic protein (MCP)-1 [24] and interleukin 6 (IL-6) [25] promoters Another mechanism of E2 repression consists of ER recruitment of a repressive complex that contains an HDAC [26]. E2 increases recruitment of HDAC1 and Sin3A, and increases methylation of CpGs. E2 down regulates cox-2 expression through a mechanism that involves a combination of decreasing activator and increasing repressor recruitment to the cox-2 promoter, and does so in a neuronal setting
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