Mechanisms by which 17β-Estradiol (E2) suppress neuronal cox-2 expression




Stacey, Winfred


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Data from animal models indicate that 17β-estradiol (E2) deprivation increases susceptibility to neurodegenerative diseases. E2 attenuates inflammatory response by suppressing expression of pro-inflammatory genes; however, the mechanisms by which E2 suppress neuronal pro-inflammatory genes are not well established. Histological analyses of postmortem human brains suggest that neuronal cyclooxygenase-2 (COX-2) is upregulated in early stages of Alzheimer’s disease (AD) and in Parkinson’s disease (PD). Given that COX-2 is selectively expressed in a subset of neurons in the hippocampus, cerebral cortex, and amygdala, we investigated mechanisms by which E2 could down-regulate cox-2 expression in a neuronal system. To characterize the effect of E2 on cox 2 in a neuronal system, we used the AR-5 and N27 rat neuronal cell line models. Our data indicate that E2 and ERβ agonist diarylpropionitrile (DPN) suppress COX-2 pre-mRNA and mRNA levels to the same extent in AR-5 but not in N27. Furthermore, PHTPP, a selective ERβ antagonist, reversed the effect of both E2 and DPN in AR-5. Because the cox-2 promoter lacks palindromic estrogen response elements (EREs), we targeted a proximal promoter region with a nuclear factor- ĸB (NF-ĸB) response element implicated in cox-2 regulation. E2 and DPN failed to increase ERβ occupancy at the cox-2 promoter. Rather, DPN decreased promoter occupancy of p65 NF-κB subunit and acetylation of histone 4 (Ac-H4). Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the effect of TSA, E2 and DPN increase HDAC1 promoter occupancy; however recruitment of HDAC3 was unchanged. HDAC1 is known to form a complex with Swi-independent A (Sin3A); E2 and DPN increased Sin3A occupancy. The recruitment of HDAC1 seems to correlate with decreased acetylation of histone 4 (H4) and not histone 3 (H3). Furthermore E2 alone increased methylation status in the cox-2 proximal promoter. Taken together, these data suggest that E2 suppresses neuronal cox-2 expression through ERβ-mediated recruitment of HDAC1, Sin3A and a concomitant reduction of p65 and H4 levels. Here we conclude that E2 suppresses neuronal cox-2 expression through a mechanism that involves a combination of decreasing activator and increasing repressor recruitment to the cox-2 promoter.