Johnson Adam B, Sohrabji Farida
Department of Anatomy and Medical Neurobiology, TAMUS Health Science Center, College of Medicine, 228 Reynolds Medical Building, College Station, TX 77843-1114, USA.
Neurobiol Aging. 2005 Nov-Dec;26(10):1365-74. doi: 10.1016/j.neurobiolaging.2004.12.006. Epub 2005 Feb 17.
Previous work from this lab has shown that estrogen attenuates inflammatory cytokine production following brain lesions in young adult female rats, but not in older, reproductive senescent females. The present study was designed to elucidate whether these effects result from estrogen's actions on brain-resident immune cells (microglia) or on circulating immune cells recruited to the brain from blood. Microglia, harvested from the olfactory bulbs of ovariectomized young adult and reproductive senescent animals, were pretreated with 17beta-estradiol and subsequently with the bacterial endotoxin LPS. LPS treatment significantly increased the pro-inflammatory cytokine IL-1beta in microglial cultures harvested from young and senescent females, but estrogen treatment had no effect on cytokine expression in either group. In young adult-derived microglia, LPS treatment also increased nitric oxide (NO), which was attenuated by estrogen, and MMP-9, which was not affected by estrogen. Reproductive senescent-derived microglia cultures had higher basal expression of NO and MMP-9 activity as compared to those from young adult microglial cultures, although LPS did not further stimulate these inflammatory markers. In blood cultures, LPS stimulated a dose-dependent increase in the inflammatory cytokine TNF-alpha expression in both young adult and reproductive senescent animals. Estrogen replacement significantly attenuated TNF-alpha induction by LPS in blood cultures derived from young adult females. Paradoxically, estrogen replacement increased LPS-induced TNF-alpha expression in blood cultures derived from reproductive senescent animals as compared to age-matched controls. The age and estrogen dependent effects on circulating immune cells found in whole blood cultures closely mimic the effects of estrogen on cytokine expression in the young and senescent animals that we reported in vivo, supporting the hypothesis that the immunosuppressive actions of estrogen replacement on neural injury may result from hormone-action on circulating immune cells.
该实验室之前的研究表明，雌激素可减轻年轻成年雌性大鼠脑损伤后的炎性细胞因子产生，但对老年生殖衰老雌性大鼠无效。本研究旨在阐明这些作用是否源于雌激素对脑内固有免疫细胞（小胶质细胞）的作用，还是对从血液募集到脑内的循环免疫细胞的作用。从小鼠卵巢切除的年轻成年和生殖衰老动物的嗅球中分离出小胶质细胞，先用17β-雌二醇预处理，随后用细菌内毒素LPS处理。LPS处理显著增加了从年轻和衰老雌性小鼠分离的小胶质细胞培养物中促炎细胞因子IL-1β的表达，但雌激素处理对两组细胞因子表达均无影响。在源自年轻成年小鼠的小胶质细胞中，LPS处理还增加了一氧化氮（NO），而雌激素可使其减弱，以及基质金属蛋白酶-9（MMP-9），其不受雌激素影响。与年轻成年小胶质细胞培养物相比，生殖衰老来源的小胶质细胞培养物中NO的基础表达和MMP-9活性更高，尽管LPS并未进一步刺激这些炎症标志物。在血液培养物中，LPS刺激年轻成年和生殖衰老动物的炎性细胞因子TNF-α表达呈剂量依赖性增加。雌激素替代显著减弱了年轻成年雌性动物血液培养物中LPS诱导的TNF-α表达。矛盾的是，与年龄匹配的对照组相比，雌激素替代增加了生殖衰老动物血液培养物中LPS诱导的TNF-α表达。全血培养物中发现的雌激素对循环免疫细胞的年龄和雌激素依赖性作用与我们在体内报道的雌激素对年轻和衰老动物细胞因子表达的作用密切相似支持了这样的假设，即雌激素替代对神经损伤的免疫抑制作用可能源于激素对循环免疫细胞的作用。
