Wang Jianping, Pham-Mitchell Ngan, Schindler Christian, Campbell Iain L
The Scripps Research Institute, SP315, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
J Clin Invest. 2003 Aug;112(4):535-43. doi: 10.1172/JCI18637.
The type I IFNs (IFN-alpha and IFN-beta), which are crucial in antiviral defense and immune regulation, signal via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway with activation of STAT1 and STAT2. Here, the function of STAT2 was studied in transgenic mice (termed GIFN/STAT2-/-) with CNS production of IFN-alpha. Surprisingly, GIFN/STAT2-/-, but not GIFN/STAT1-null, transgenic mice, with CNS production of IFN-alpha, died prematurely with medulloblastoma. An immune response also induced in the brain of the GIFN/STAT2-/- mice was associated with IFN-gamma gene expression by CD3+ T cells and the activation of the STAT1, STAT3, STAT4, and STAT5 molecules. Expression of the Sonic hedgehog (Shh) and the downstream transcriptional factor Gli-1 genes, implicated in the pathogenesis of medulloblastoma, was found to be significantly increased and cotranscribed in cerebellar granule neurons of the GIFN/STAT2-/- mice. IFN-gamma, but not IFN-alpha, induced STAT1-dependent expression of the Shh gene in cultured cerebellar granule neurons. Thus, there is an unexpected and extraordinarily adverse biological potency of IFN-alpha in the CNS when the primary signal transduction molecule STAT2 is absent. Moreover, a hitherto unknown role is indicated for the immune system in the pathogenesis of developmental disorders and tumorigenesis of the CNS via dysregulated Shh signaling mediated by IFN-gamma.
I型干扰素（IFN-α和IFN-β）在抗病毒防御和免疫调节中起关键作用，通过激活STAT1和STAT2的Janus激酶/信号转导子和转录激活子（JAK/STAT）途径进行信号传导。在此，研究了STAT2在中枢神经系统产生IFN-α的转基因小鼠（称为GIFN/STAT2-/-）中的功能。令人惊讶的是，中枢神经系统产生IFN-α的GIFN/STAT2-/-转基因小鼠而非GIFN/STAT1基因敲除小鼠过早死于髓母细胞瘤。GIFN/STAT2-/-小鼠大脑中诱导的免疫反应与CD3+T细胞的IFN-γ基因表达以及STAT1、STAT3、STAT4和STAT5分子的激活有关。发现与髓母细胞瘤发病机制相关的音猬因子（Shh）和下游转录因子Gli-1基因的表达在GIFN/STAT2-/-小鼠的小脑颗粒神经元中显著增加并共同转录。IFN-γ而非IFN-α在培养的小脑颗粒神经元中诱导Shh基因的STAT1依赖性表达。因此，当主要信号转导分子STAT2缺失时，IFN-α在中枢神经系统中具有意想不到且极其有害的生物学效应。此外，免疫系统通过IFN-γ介导的失调Shh信号传导在中枢神经系统发育障碍和肿瘤发生的发病机制中显示出迄今未知的作用。
