A NULL MUTATION IN THE GENE ENCODING A TYPE-I INTERFERON RECEPTOR COMPONENT ELIMINATES ANTIPROLIFERATIVE AND ANTIVIRAL RESPONSES TO INTERFERON-ALPHA AND INTERFERON-BETA AND ALTERS MACROPHAGE RESPONSES
A NULL MUTATION IN THE GENE ENCODING A TYPE-I INTERFERON RECEPTOR COMPONENT ELIMINATES ANTIPROLIFERATIVE AND ANTIVIRAL RESPONSES TO INTERFERON-ALPHA AND INTERFERON-BETA AND ALTERS MACROPHAGE RESPONSES
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DOI：
10.1073/pnas.92.24.11284
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发表时间：
1995-11-21
影响因子：
11.1
通讯作者：
KOLA, I
中科院分区：
文献类型：
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作者：
HWANG, SY;HERTZOG, PJ;KOLA, I
为了研究I型干扰素（IFNs）在体内的作用，并确定I型干扰素受体（IFNAR1）的一个组分在介导对这些干扰素的反应中的作用，我们构建了IFNAR1基因缺失突变（-/-）的小鼠。尽管有令人信服的证据表明I型干扰素可调节细胞增殖和分化，但在成年IFNAR1 -/-小鼠中没有明显的胎儿发育异常迹象或形态学改变。然而，在IFNAR1 -/-小鼠中检测到造血细胞异常。通过用Mac - 1和Gr - 1抗体染色，在外周血和骨髓中检测到髓系细胞水平升高。此外，来自IFNAR1 -/-小鼠的骨髓巨噬细胞对集落刺激因子1和脂多糖表现出异常反应。IFNAR1 -/-小鼠对病毒感染高度易感：在IFNAR1 +/+小鼠感染24小时后未检测到病毒滴度，但在IFNAR1 -/-小鼠的器官中病毒滴度极高，这表明I型干扰素系统是一种主要的急性抗病毒防御机制。在源自IFNAR1 -/-小鼠的细胞系中，通过检测2'-5'寡腺苷酸合成酶的诱导、抗病毒或抗增殖反应，未发现对IFN -α或 -β有信号传导。重要的是，这些研究表明I型干扰素在髓系细胞（特别是巨噬细胞）的发育和反应中起作用，并且IFNAR1受体组分对IFN -α和 -β的抗增殖和抗病毒反应至关重要。
To examine the in vivo role(s) of type I interferons (IFNs) and to determine the role of a component of the type I IFN receptor (IFNAR1) in mediating responses to these IFNs, we generated mice with a null mutation (-/-) in the IFNAR1 gene. Despite compelling evidence for modulation of cell proliferation and differentiation by type I IFNs, there were no gross signs of abnormal fetal development or morphological changes in adult IFNAR1 -/- mice. However, abnormalities of hemopoietic cells were detected in IFNAR1 -/- mice, Elevated levels of myeloid lineage cells were detected in peripheral blood and bone marrow by staining with Mac-1 and Gr-1 antibodies, Furthermore, bone marrow macrophages from IFNAR1 -/- mice showed abnormal responses to colony-stimulating factor 1 and lipopolgsaccharide. IFNAR1 -/- mice were highly susceptible to viral infection: viral titers were undetected 24 hr after infection of IFNAR1 +/+ mice but were extremely high in organs of IFNAR1 -/- mice, demonstrating that the type I IFN system is a major acute antiviral defence, In cell lines derived from IFNAR1 -/- mice, there was no signaling in response to IFN-alpha or -beta as measured by induction of 2'-5' oligooadenylate synthetase, antiviral, or antiproliferative responses. Importantly, these studies demonstrate that type I IFNs function in the development and responses of myeloid lineage cells, particularly macrophages, and that the LFNAR1 receptor component is essential for antiproliferative and antiviral responses to IFN-alpha and -beta.