Deregulation of IRF Menbers in Human Retroviral Infection

IRF 成员在人类逆转录病毒感染中的放松管制

• 批准号: 08044259
• 负责人: MATSUYAMA Toshifumi
• 金额: $ 4.67万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08044259/
• 关键词: Human retroviral infection; Interferon; インターフェロン調節因子; ヒトレトロウイルス; ATL; IRF; 遺伝子欠損マウス

In this study, we focused on the role of Interferon Regulatory Factor ( IRF ) family members in retroviral infection. First we could demonstrate the essential role of LSIRF/IRF-4, an IRF member solely expressed in mature lymphocytes, in T and B function by the development of the gene targeted mouse. In this mutant mouse, the number of T and B lymphocytes is normal, but disable to mount proliferative responses against mitogens or anti-CD3 antibodies or alloantigens. In human, constitutive expression of LSIRF/lRF-4 is found only in cells infected with HTLV-1 , a causative agent of adult leukemia/lymphoma which is prevalent in our Nagasaki area. From clinical analysis, high-expression level is well correlated with the leukemic stage of the patients of ATL, suggesting the possible marker for prognosis in the disease as well as the role of the factor in leukemia as an oncogene. However, many efforts to clone a stable transformant with ectopically expressed LSIRF/lRF-4 is unsuccessful. Developing an inducible expression system of LSIRF/lRF-4, and isolating its associated factor (s) by yeast two-hybrid systems are now in progress.In case of IRF-1 deficient mouse, poor development of NK cells and low expression of IL-1 5 was found. The latter caused by the defect of IRF-1 expression, at least in part, seems to contribute to the impairment of NK cells development. It is interesting to seek physiological conditions of low expression of IRF-1 , by which individuals are susceptible to viral infection in general. On the other hand, this mutant mouse is resistant to a experimental model of human multiple sclerosis, a disease suggestedly caused by retroviral infection, implying that individuals protect themselves against retroviral infection by induction of IRF-1 at the risk of some autoimmune disease involvement.

本研究主要探讨干扰素调节因子（IRF）家族成员在逆转录病毒感染中的作用。首先，我们可以证明LSIRF/IRF-4，一个只在成熟淋巴细胞中表达的IRF成员，在T和B功能中的重要作用。在这种突变小鼠中，T和B淋巴细胞的数量是正常的，但不能对有丝分裂原或抗CD 3抗体或同种异体抗原产生增殖反应。在人类中，LSIRF/lRF-4的组成型表达仅在HTLV-1感染的细胞中发现，HTLV-1是成人白血病/淋巴瘤的病原体，在我们的长崎地区流行。从临床分析来看，高表达水平与ATL患者的白血病分期密切相关，提示该因子可能是疾病预后的标志物，也可能作为癌基因在白血病中发挥作用。然而，许多克隆具有异位表达的LSIRF/IRF-4的稳定细胞的努力是不成功的。IRF-1缺陷小鼠NK细胞发育不良，IL-15表达降低，后者可能是IRF-1表达缺陷所致，至少部分是由于IRF-1表达缺陷所致。寻找IRF-1低表达的生理条件是令人感兴趣的，通过该生理条件，个体通常易受病毒感染。另一方面，这种突变小鼠对人类多发性硬化症的实验模型具有抗性，多发性硬化症是一种由逆转录病毒感染引起的疾病，这意味着个体通过诱导IRF-1来保护自己免受逆转录病毒感染，但有一些自身免疫性疾病参与的风险。

项目成果

Mittrucker H. W., et al: "Requirement for the transcription factor LSIRF/IRF-4 for mature B and T lymphocyte function." Science. 275. 540-543 (1997)

Mittrucker H. W. 等人：“成熟 B 和 T 淋巴细胞功能需要转录因子 LSIRF/IRF-4。”

Tada Y., et al: "Reduced incidence and severity of antigen-induced autoimmune diseases in mice lacking IRF-1" J. Exp. Med.185. 231-238 (1997)

Tada Y. 等人：“缺乏 IRF-1 的小鼠中抗原诱导的自身免疫性疾病的发生率和严重程度降低”J. Exp。

Mittrucker H.W: "Requirement for the transcription factor LSIRF/IRF-4 for mature B and T lymphocyte function." Science. 275. 540-543 (1997)

Mittrucker H.W：“成熟 B 和 T 淋巴细胞功能需要转录因子 LSIRF/IRF-4。”

Tanaka N., et al.: "Cooperation of the tumor suppressors IRF-1 and p53 in response to DNA damage" Nature. 382. 816-818 (1996)

Tanaka N. 等人：“肿瘤抑制因子 IRF-1 和 p53 响应 DNA 损伤的合作”Nature。

Tada Y, et al.: "Reduced incidence and severity of antigen-induced autoimmune diseases in mice lacking IRF-1"J. Exp. Med.. 185. 231-238 (1997)

Tada Y 等人：“缺乏 IRF-1 的小鼠中抗原诱导的自身免疫性疾病的发生率和严重程度降低”J.