Sundar S K, Cierpial M A, Kamaraju L S, Long S, Hsieh S, Lorenz C, Aaron M, Ritchie J C, Weiss J M
Department of Psychiatry, Duke University Medical Center, Durham, NC 27710.
Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11246-50. doi: 10.1073/pnas.88.24.11246.
Intracerebroventricular (i.c.v.) infusion of glycosylated recombinant gp120, the envelope protein of human immunodeficiency virus, in various doses (100 ng to 4 micrograms) resulted in detection of interleukin 1 (IL-1) activity in a high percentage (61%; 33 of 54) of rat brains, whereas IL-1 was very rarely detected in brains of animals infused with several control substances (4%; 1 of 28). To detect IL-1, clarified glial lysate of diencephalon plus brainstem was subjected to gel exclusion chromatography and fractions were assessed for thymocyte stimulation. IL-1 was seen 2, 6, and 24 hr postinfusion. i.c.v. gp120 also produced known effects of IL-1 in brain, elevating steroid concentration in plasma and decreasing cellular immune responses [natural killer (NK) cell activity and mitogenic response to Con A] of blood and splenic lymphocytes. When gp120 was infused together with alpha-melanocyte-stimulating hormone (20 ng), which blocks many biological actions of IL-1, gp120 no longer elevated steroids or decreased NK cell activity. After intravenous gp120, IL-1 was not found in brain or plasma, indicating that stimulation of IL-1 in brain by i.c.v. gp120 was not due to gp120 affecting infiltrating cells from blood or to elevated circulating IL-1. That induction of IL-1 in brain might have resulted from lipopolysaccharide (LPS) in the gp120 solution was ruled out by studies showing that (i) heating of the infusion solution, which does not affect the capacity of LPS to induce IL-1, eliminated the ability of gp120 infusion to induce brain IL-1, and (ii) gp120 induced IL-1 in brains of LPS-resistant C3H/HeJ mice. Injection of gp120 directly into the hippocampus stimulated IL-1 more readily than i.c.v. infusion. Thymocyte stimulation produced by active fractions of gp120-infused brains was blocked by monoclonal antibody to IL-1 receptors. These findings indicate that elevation of IL-1 in brain can result from infection with human immunodeficiency virus and may be responsible for certain abnormalities (e.g., elevated activity of pituitary-adrenal axis) seen in AIDS patients.
向大鼠脑室内（i.c.v.）注射不同剂量（100纳克至4微克）的糖基化重组人免疫缺陷病毒包膜蛋白gp120后，在很大比例（61%；54只中有33只）的大鼠脑中检测到白细胞介素1（IL-1）活性，而在注射几种对照物质的动物脑中很少检测到IL-1（4%；28只中有1只）。为了检测IL-1，将间脑加脑干的澄清神经胶质裂解物进行凝胶排阻色谱分析，并对各组分进行胸腺细胞刺激评估。在注射后2小时、6小时和24小时均检测到IL-1。脑室内注射gp120还产生了IL-1在脑中的已知效应，即提高血浆中类固醇浓度，并降低血液和脾淋巴细胞的细胞免疫反应[自然杀伤（NK）细胞活性和对刀豆蛋白A的促有丝分裂反应]。当将gp120与能阻断IL-1许多生物学作用的α-黑素细胞刺激素（20纳克）一起注射时，gp120不再提高类固醇水平或降低NK细胞活性。静脉注射gp120后，在脑或血浆中未发现IL-1，这表明脑室内注射gp120对脑内IL-1的刺激不是由于gp120影响来自血液的浸润细胞或循环中IL-1升高所致。表明脑内IL-1的诱导可能是由gp120溶液中的脂多糖（LPS）引起的这一观点，被以下研究所排除：（i）加热注射溶液，这并不影响LPS诱导IL-1的能力，但消除了gp120注射诱导脑内IL-1的能力；（ii）gp120在LPS抗性C3H/HeJ小鼠的脑中诱导IL-1。将gp120直接注射到海马体中比脑室内注射更容易刺激IL-1。注射gp120的脑的活性组分产生的胸腺细胞刺激被抗IL-1受体单克隆抗体阻断。这些发现表明，脑内IL-1升高可能是由人类免疫缺陷病毒感染引起的，并且可能是艾滋病患者中出现的某些异常情况（例如垂体-肾上腺轴活性升高）的原因。
