LaFerla F M, Sugarman M C, Lane T E, Leissring M A
Department of Neurobiology and Behavior, University of California, Irvine 92697-4545, USA.
J Mol Neurosci. 2000 Aug;15(1):45-59. doi: 10.1385/JMN:15:1:45.
Interferon-gamma (IFN-gamma), traditionally associated with a variety of physiological and pathological processes of the immune system, manifests an array of biological effects on cells of the nervous system. Clinical and in vitro studies support a key role for IFN-gamma in the pathogenesis of immune-mediated demyelinating disorders such as multiple sclerosis (MS). To investigate the role of this cytokine within the central nervous system (CNS), transgenic mice were derived in which IFN-gamma transgene expression was selectively targeted to astrocytes, a potentially important cellular source of this cytokine. Here we report that astrocyte-directed expression of IFN-gamma results in regional hypomyelination and selective disruption of brain histogenesis, which included severe cerebellar and hippocampal dysplasia. Transgenic mice were markedly ataxic and the majority died prior to reaching sexual maturity. This study demonstrates that astrocyte-directed expression of IFN-gamma profoundly affects the differentiation and morphogenesis of the brain and provides additional evidence that this cytokine has deleterious consequences on myelin-producing cells, independent of the cellular source.
传统上，干扰素-γ（IFN-γ）与免疫系统的多种生理和病理过程相关，它对神经系统细胞具有一系列生物学效应。临床和体外研究支持IFN-γ在免疫介导的脱髓鞘疾病（如多发性硬化症，MS）发病机制中起关键作用。为了研究这种细胞因子在中枢神经系统（CNS）中的作用，构建了转基因小鼠，其中IFN-γ转基因表达被选择性地靶向星形胶质细胞，星形胶质细胞是这种细胞因子潜在的重要细胞来源。在此我们报告，星形胶质细胞定向表达IFN-γ会导致局部髓鞘形成减少和脑组织发生的选择性破坏，其中包括严重的小脑和海马发育异常。转基因小鼠明显共济失调，大多数在达到性成熟之前死亡。这项研究表明，星形胶质细胞定向表达IFN-γ会深刻影响大脑的分化和形态发生，并提供了额外证据，证明这种细胞因子对产生髓鞘的细胞具有有害影响，且与细胞来源无关。
