Moynagh P N, Williams D C, O'Neill L A
Department of Biochemistry and Biotechnology Institute, Trinity College, University of Dublin, Ireland.
J Immunol. 1994 Sep 15;153(6):2681-90.
The infiltration of leukocytes into the central nervous system is associated with many pathologic conditions of the brain. The mechanisms by which these immune cells can penetrate the blood-brain barrier and remain within the brain are not understood. However, elevated brain levels of the pro-inflammatory cytokine IL-1 appear to accompany pathogenesis. The present study provides the first evidence that IL-1 can induce the expression of adhesion molecules for leukocytes on glial cells and suggests a role for the transcription factor NF-kappa B in the induction process. Human rIL-1 alpha was found to induce the expression of the cell adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) but not E-selectin in human 1321N1 astrocytoma. Both VCAM-1 and ICAM-1 were detectable from 3 h and remained sustained for up to 72 h. Induction was inhibited by the IL-1 receptor antagonist. IL-1 alpha was also shown to induce the expression of VCAM-1 and ICAM-1 in a receptor-dependent fashion in human A172 glioblastoma. Activation of the transcription factor NF-kappa B was also observed in 1321N1 astrocytoma in response to IL-1 alpha treatment and was similarly abolished by pretreatment of cells with antagonist. Activated NF-kappa B was apparent from 20 min and remained for up to 24 h. N-acetylcysteine (NAC) and pyrollidinedithiocarbamate (PDTC), which were shown to inhibit activation of NF-kappa B in Jurkat E6.1 lymphoblasts and EL4.NOB-1 thymoma, failed to block IL-1 activation of NF-kappa B in 1321N1 astrocytoma. However, both of these antioxidants demonstrated complex modulatory effects on the induction of cell adhesion molecule expression by IL-1. The induction of VCAM-1 but not of ICAM-1 proved susceptible to inhibition by both PDTC and NAC. The expression of adhesion molecules for leukocytes on glial cells in response to IL-1 may represent an important mechanism for retention of immune cells in the central nervous system that may be a prologue to inflammatory conditions in the brain.
白细胞浸润中枢神经系统与许多脑部病理状况相关。这些免疫细胞穿透血脑屏障并留存于脑内的机制尚不清楚。然而，促炎细胞因子IL-1在脑内水平升高似乎与发病机制相伴。本研究首次提供证据表明，IL-1可诱导神经胶质细胞上白细胞黏附分子的表达，并提示转录因子NF-κB在诱导过程中发挥作用。研究发现，人重组IL-1α可诱导人1321N1星形细胞瘤中细胞黏附分子血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1）的表达，但不诱导E-选择素的表达。VCAM-1和ICAM-1在3小时时均可检测到，并持续长达72小时。诱导作用被IL-1受体拮抗剂抑制。IL-1α还被证明以受体依赖方式诱导人A172胶质母细胞瘤中VCAM-1和ICAM-1的表达。在用IL-1α处理的1321N1星形细胞瘤中也观察到转录因子NF-κB的激活，并且用拮抗剂预处理细胞同样可消除这种激活。活化的NF-κB在20分钟时明显出现，并持续长达24小时。已证明可抑制Jurkat E6.1淋巴母细胞和EL4.NOB-1胸腺瘤中NF-κB激活的N-乙酰半胱氨酸（NAC）和吡咯烷二硫代氨基甲酸盐（PDTC），未能阻断1321N1星形细胞瘤中IL-1对NF-κB的激活。然而，这两种抗氧化剂均对IL-1诱导细胞黏附分子表达表现出复杂的调节作用。事实证明，PDTC和NAC均可抑制VCAM-1而非ICAM-1的诱导。神经胶质细胞上白细胞黏附分子对IL-1的应答表达可能代表免疫细胞留存于中枢神经系统的一种重要机制，这可能是脑部炎症状况的前奏。
