Expression of ICAM-1, TNF-α, NFκB, and MAP kinase in tubers of the tuberous sclerosis complex
Expression of ICAM-1, TNF-α, NFκB, and MAP kinase in tubers of the tuberous sclerosis complex
复制标题
DOI：
10.1016/s0969-9961(03)00127-x
复制
发表时间：
2003-11-01
影响因子：
6.1
通讯作者：
Crino, PB
中科院分区：
文献类型：
--
作者：
Maldonado, M;Baybis, M;Crino, PB
患有结节性硬化症（TSC）的个体发展出皮质结节，其特征在于紊乱的细胞结构和形态异常的细胞类型，例如发育不良的神经元（DN）和巨细胞（GC）。作为正在进行的cDNA阵列分析的一部分，研究块茎形成的分子发病机制，我们检测到细胞间粘附分子-1（ICAM-1）mRNA的表达增加，细胞粘附分子（CAM）的细胞因子信号传导的功能，在块茎。Western和免疫组化分析显示，ICAM-1蛋白选择性表达在块茎，但只有最低限度地表达在控制皮质，相邻的非结节皮质，或在非TSC局灶性皮质发育不良。在星形胶质细胞中Tsc 1基因被条件性失活的小鼠中发现ICAM-1表达增加。在块茎中参与ICAM-1活化和细胞因子信号传导的分子的表达增加，包括肿瘤坏死因子α（TNF-α）、丝裂原活化蛋白激酶（MAPK）和核因子κ B（NF-κ B）。观察到许多CD 68免疫反应性巨噬细胞聚集在GC周围，进一步支持块茎中的炎症反应。caspase 8和Fas的表达支持细胞因子活化，TUNEL反应性的检测表明块茎中正在进行的细胞死亡。ICAM-1、TNF-α、NF-κ B1和MAPK表达的特异性改变以及大量CD 68免疫反应性巨噬细胞的检测表明块茎中促炎细胞因子信号通路的激活可能导致细胞死亡。(C)2003年爱思唯尔公司All rights reserved.
Individuals affected with tuberous sclerosis complex (TSC) develop cortical tubers characterized by disorganized cytoarchitecture and morphologically abnormal cell types, such as dysplastic neurons (DNs) and giant cells (GCs). As part of ongoing cDNA array analysis to study the molecular pathogenesis of tuber formation, we detected increased expression of intercellular adhesion molecule-1 (ICAM-1) mRNA, a cell adhesion molecule (CAM) that functions in cytokine signaling, in tubers. Western and immunohistochemical analyses revealed that ICAM-1 protein was selectively expressed in tubers, but was only minimally expressed in control cortex, adjacent nontuberal cortex, or in non-TSC focal cortical dysplasia. Increased expression of ICAM-1 was found in mice in which the Tsc1 gene was conditionally inactivated in astrocytes. Expression of molecules involved in ICAM-1 activation and cytokine signaling were increased in tubers, including tumor necrosis factor alpha (TNF-alpha), mitogen activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB). Numerous CD68-immumoreactive macrophages were observed clustered around GCs further supporting an inflammatory response in tubers. Expression of caspase 8 and Fas support cytokine activation and detection of TUNEL reactivity suggests ongoing cell death in tubers. Specific alterations in ICAM-1, TNF-alpha, NF-kappaB1, and MAPK expression coupled with the detection of numerous CD68-immumoreactive macrophages suggests activation of proinflammatory cytokine signaling pathways in tubers that may culminate in cell death. (C) 2003 Elsevier Inc. All rights reserved.