Klores Molly, Moon John T, Duncan Kelli A
Vassar College, Poughkeepsie, NY 12604, USA.
Vassar College, Poughkeepsie, NY 12604, USA; Department of Biology, Poughkeepsie, NY 12604, USA.
J Chem Neuroanat. 2017 Jan;79:32-37. doi: 10.1016/j.jchemneu.2016.11.002. Epub 2016 Nov 5.
Under neurodegenerative conditions, reactive astrocytes upregulate both aromatase (estrogen synthase) as well as estrogen and androgen receptors. This increased steroidogenic signal promotes neuroprotection and repair by promoting neurogenesis and decreasing cell death, but also by modulating the release of inflammatory molecules. Thus, endocrine - immune cross-talk is an essential component of estrogen mediated neuroprotection following brain injury. However, the exact mechanisms underlying this cross-talk remains unknown. cAMP response element-binding protein-binding protein (CBP) may be involved in the modulation of both the endocrine and inflammatory response following injury. CBP acts as both an estrogen receptor (ER) coactivator and as a promotor for NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) target genes and previous data suggests that ER and NF-κB compete for CBP. When CBP is displaced, target genes for NF-κB are repressed and inflammation is decreased. To test the role of CBP following injury, we examined CBP expression following penetrating injury in adult male and female zebra finches. Using immunohistochemistry, we were able to specifically examine glial CBP expression, as glial cells are important mediators of the neuroendocrine response to damage. Male but not female zebra finches upregulated glial CBP following damage to the brain. To determine if this upregulation was estrogen dependent, we decreased local estrogen levels with fadrozole (aromatase inhibitor) and reexamined glial CBP expression following injury. Aromatase inhibition resulted in no change in overall glial CBP expression suggesting that circulating estrogens do not mediate the upregulation of glial CBP following injury. Thus CBP may play a role in the both the estrogen and immune response to injury.
在神经退行性疾病状态下，反应性星形胶质细胞会上调芳香化酶（雌激素合成酶）以及雌激素和雄激素受体。这种增强的类固醇生成信号通过促进神经发生和减少细胞死亡，以及调节炎症分子的释放来促进神经保护和修复。因此，内分泌 - 免疫相互作用是脑损伤后雌激素介导的神经保护的重要组成部分。然而，这种相互作用的确切机制仍不清楚。环磷酸腺苷反应元件结合蛋白结合蛋白（CBP）可能参与损伤后内分泌和炎症反应的调节。CBP既是雌激素受体（ER）的共激活因子，又是核因子κB（活化B细胞的轻链增强子核因子）靶基因的启动子，先前的数据表明ER和NF-κB竞争CBP。当CBP被取代时，NF-κB的靶基因被抑制，炎症减少。为了测试损伤后CBP的作用，我们检查了成年雄性和雌性斑胸草雀穿透性损伤后的CBP表达。使用免疫组织化学，我们能够特异性地检查胶质细胞CBP的表达，因为胶质细胞是对损伤的神经内分泌反应的重要介质。雄性而非雌性斑胸草雀在脑损伤后上调了胶质细胞CBP。为了确定这种上调是否依赖于雌激素，我们用法倔唑（芳香化酶抑制剂）降低局部雌激素水平，并在损伤后重新检查胶质细胞CBP的表达。芳香化酶抑制导致胶质细胞CBP的总体表达没有变化，这表明循环雌激素不介导损伤后胶质细胞CBP的上调。因此，CBP可能在损伤的雌激素和免疫反应中都发挥作用。
