Analysis of the genetic network in the host difence system.

目前的研究主要集中在阐明宿主防御调控的分子机制，包括免疫系统调控和肿瘤发生。首先，我们研究了IRF家族转录因子，即IRF-1和p48 （ISGF3_< γ >）的作用，使用这些因子缺乏的小鼠。研究发现(i) IRF-1和p48（在ISGF3复合物的背景下）对于IFN- α / β和IFN-_< γ >的抗病毒反应是必需的，（ii） 9这些因子也参与IFN-a/B基因的表达，（iii） IRF-1而不是p48对于诱导Th1型免疫反应和自然杀伤细胞的发育是必需的。事实上，IRF-1已被证明对IL-12和IL-15基因的转录诱导至关重要。此外，我们发现IRF-1在正常成纤维细胞和携带活化癌基因的成纤维细胞中具有肿瘤抑制作用，IRF-1与p53协同诱导细胞周期阻滞和细胞凋亡。IRF-1也被证明是诱导DNA损伤诱导的增殖T细胞凋亡所必需的。我们还发现了ifn - α / β的新的抗病毒功能，即在病毒感染的细胞中选择性诱导细胞凋亡。关于IL-2诱导淋巴细胞增殖的机制，我们发现Jak1和Jak3蛋白酪氨酸激酶（PTKs）是与IL-2受体（IL-2R）体偶联的关键分子。事实上，我们引用的证据表明，il -2诱导的这些PTKs的激活对于增殖性信号传递是必不可少的。此外，我们发现Pyk2 PTK是Jak通路的一个重要下游分子。我们还提供了IL-2信号的下游靶基因，即c- myc和Bcl-2在促进细胞周期中的合作证据。这些结果有助于我们对宿主防御中细胞反应的分子机制的理解。

The present study has been focused on the elucidation of the molecular mechanisms underlying requlation of host defense, including the regulation of the immune system and oncogenesis.First, we studied the roles of the IRF family transcription factors, i.e.IRF-1 and p48 (ISGF3_<gamma>), using mice deficient in these factors. It was found that (i) both IRF-1 and p48 (in the context of the ISGF3 complex) are essential for the antiviral response of IFN-alpha/beta and IFN-_<gamma>, (ii) 9 these factors are also involved in the expression of the IFN-a/B genes, (iii) IRF-1, but not p48, is essential for the induction of the Th1 type immune response and development of natural killer cells. In fact, IRF-1 has been shown to be essential for the transcriptional induction of IL-12 and IL-15 genes. In addition, we discovered that IRF-1 functions as atumor suppressor, and that IRF-1 cooperates with p53 to induce cell cycle arrest and apoptosis in normal fibroblasts or fibroblasts carrying an activated oncogene, respectively. IRF-1 was also shown to be essential for the induction of apoptosis of DNA damage-induced, proliferating T cells. We aldo discovered anovel anti-viral function of IFN-alpha/beta, i.e.selective induction of apoptosis in virally infected cells.Regarding to the mechanisms of the IL-2-induced lymphocyte proliferation, we identified Jak1 and Jak3 protein tyrosine kinases (PTKs) as the crucial molecules coupling with the IL-2 receptor (IL-2R) somplex. Indeed, we adduced evidence that the IL-2-induced activation of these PTKs is essential for proliferative signal transmission. Furthermore, we identified Pyk2 PTK as a crucial downstream molecule of the Jak pathway. We also provided evidence for cooperation of the downstream target genes of the IL-2 signaling, i.e.c-Myc and Bcl-2, in promotion of the cell cycle.These results in to contribute to our understanding of the molecular mechanisms of cellular responses in the host defense.