School of Biochemistry and Immunology and Trinity College Institute of Neuroscience, Trinity College, Dublin, Republic of Ireland.
PLoS One. 2013 Jul 1;8(7):e69123. doi: 10.1371/journal.pone.0069123. Print 2013.
It is increasingly clear that systemic inflammation has both adaptive and deleterious effects on the brain. However, detailed comparisons of brain effects of systemic challenges with different pro-inflammatory cytokines are lacking. In the present study, we challenged female C57BL/6 mice intraperitoneally with LPS (100 µg/kg), IL-1β (15 or 50 µg/kg), TNF-α (50 or 250 µg/kg) or IL-6 (50 or 125 µg/kg). We investigated effects on core body temperature, open field activity and plasma levels of inflammatory markers at 2 hours post injection. We also examined levels of hepatic, hypothalamic and hippocampal inflammatory cytokine transcripts. Hypothermia and locomotor hypoactivity were induced by LPS>IL-1β>TNF-α>>IL-6. Systemic LPS, IL-1β and TNF-α challenges induced robust and broadly similar systemic and central inflammation compared to IL-6, which showed limited effects, but did induce a hepatic acute phase response. Important exceptions included IFNβ, which could only be induced by LPS. Systemic IL-1β could not induce significant blood TNF-α, but induced CNS TNF-α mRNA, while systemic TNF-α could induce IL-1β in blood and brain. Differences between IL-1β and TNF-α-induced hippocampal profiles, specifically for IL-6 and CXCL1 prompted a temporal analysis of systemic and central responses at 1, 2, 4, 8 and 24 hours, which revealed that IL-1β and TNF-α both induced the chemokines CXCL1 and CCL2 but only IL-1β induced the pentraxin PTX3. Expression of COX-2, CXCL1 and CCL2, with nuclear localisation of the p65 subunit of NFκB, in the cerebrovasculature was demonstrated by immunohistochemistry. Furthermore, we used cFOS immunohistochemistry to show that LPS, IL-1β and to a lesser degree, TNF-α activated the central nucleus of the amygdala. Given the increasing attention in the clinical literautre on correlating specific systemic inflammatory mediators with neurological or neuropsychiatric conditions and complications, these data will provide a useful resource on the likely CNS inflammatory profiles resulting from systemic elevation of particular cytokines.
越来越明显的是，全身炎症对大脑既有适应性影响，也有有害影响。然而，缺乏对具有不同促炎细胞因子的全身挑战的大脑影响的详细比较。在本研究中，我们通过腹腔内注射 LPS（100μg/kg）、IL-1β（15 或 50μg/kg）、TNF-α（50 或 250μg/kg）或 IL-6（50 或 125μg/kg）来挑战雌性 C57BL/6 小鼠。我们在注射后 2 小时测量核心体温、旷场活动和血浆中炎症标志物的水平，还检测了肝、下丘脑和海马中的炎症细胞因子转录物水平。LPS>IL-1β>TNF-α>>IL-6 引起体温过低和运动活动减少。与 IL-6 相比，全身 LPS、IL-1β和 TNF-α 引起的全身和中枢炎症更为强烈和广泛相似，而 IL-6 则表现出有限的作用，但确实诱导了肝急性期反应。重要的例外包括 IFNβ，它只能由 LPS 诱导。全身 IL-1β不能诱导显著的血液 TNF-α，但诱导 CNS TNF-α mRNA，而全身 TNF-α可以在血液和大脑中诱导 IL-1β。IL-1β 和 TNF-α 诱导的海马图谱之间的差异，特别是对 IL-6 和 CXCL1 的差异，促使我们在 1、2、4、8 和 24 小时进行系统和中枢反应的时间分析，结果表明，IL-1β 和 TNF-α 均诱导趋化因子 CXCL1 和 CCL2，但只有 IL-1β 诱导五聚素 PTX3。通过免疫组织化学显示，COX-2、CXCL1 和 CCL2 的表达以及 NFκB 的 p65 亚基的核定位存在于脑血管中。此外，我们使用 cFOS 免疫组织化学显示 LPS、IL-1β 和在较小程度上 TNF-α 激活了杏仁核中央核。鉴于临床文献中越来越关注将特定的全身炎症介质与神经或神经精神疾病和并发症相关联，这些数据将为全身升高特定细胞因子可能导致的中枢神经系统炎症图谱提供有用的资源。
