Physiological function and Molecular mechanism of regulation by the CIS/JAB family members

CIS/JAB家族成员的生理功能及调控分子机制

基本信息

批准号：
11694329
负责人：
YOSHIMURA Akihkio
金额：
$ 5.12万
依托单位：
Kurume University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694329/
关键词：
tyrosine kinase JAK STAT CIS cytokine knockout mice tyrosine phosphorylation kinase inhibitor

项目摘要

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. We recently identified two intrinsic JAK inhibitors, JAB (also referred to as SOCS1/SSI1) and CIS3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have shown that JAB is strongly induced by interferon-γ. JAB deficient mice die perinatally with altered lymphoid development including the generation of activated T cells in vivo. The lethality is eliminated on a Rag2 or interferon-γdeficient background. Based on the results, we propose that JAB plays an essential role in negative feedback regulation of interferon-γ.During embryonic development CIS3 is highly expressed in some but not all erythroid lineage cells of the fetal liver. Deletion of CIS3 gene results in an embryonic lethality at 12-16 days that is associat … More ed with a marked erythrocytosis. Moreover, the individual in vitro proliferative capacity of fetal liver progenitors is greatly increased. The results suggest a specific negative regulatory effect of CIS3 on EPO signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, we found that STAT3 showed the strongest tyrosine phosphorylation in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of DSS-induced colitis as well as STAT3 activation was significantly reduced in IL6-deficient mice, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB-transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in acute intestinal inflammation by down-regulating STAT3 activity. Less

免疫和炎症系统受多种细胞因子的控制，包括白介氨酸（ILS）和干扰素。这些细胞因子通过Janus酪氨酸激酶和Stat转录因子发挥其生物学功能。我们最近确定了两个固有的JAK抑制剂，JAB（也称为SOCS1/SSI1）和CIS3（或SOCS3/SSI3），它们在细胞因子信号的负调控中起着至关重要的作用。我们已经表明，干扰素-γ强烈诱导了戳刺。 jab缺乏小鼠在周围死亡，随着淋巴样的发育改变，包括体内活化的T细胞的产生。在RAG2或干扰素缺陷的背景上消除了致死性。基于结果，我们建议JAB在干扰素-γ的负反馈调控中起着至关重要的作用。D胚胎发育CIS3在某些但并非所有的胎儿肝脏丝状谱系细胞中都高度表达。 CIS3基因的缺失导致12-16天的胚胎致死性，这是相关的……更具有明显的红细胞增多症。此外，胎儿肝祖细胞的体外增殖能力大大增加。结果表明CIS3对EPO信号传导产生了特定的负调控作用。我们已经调查了数据和这些JAK抑制剂在肠道注射中的作用。在STAT家族成员中，我们发现STAT3在人溃疡性结肠炎和克罗恩病患者以及硫酸葡萄酸钠（DSS）诱导的小鼠中的强烈酪氨酸磷酸化以及小鼠中的硫酸葡萄球菌磷酸化。 IL6缺陷小鼠的DSS诱导的结肠炎以及STAT3激活的发展显着降低，这表明STAT3在结肠炎的持久性中起着重要作用。 CIS3，但不是JAB，在DSS处理的小鼠的结肠中高度表达。为了定义CIS3诱导在结肠炎中的物理作用，我们开发了一种刺戳突变体（F59D-JAB），该突变体克服了jab和cis3的抑制作用，并产生了转基因小鼠。与野生型同窝仔相比，DSS诱导F59D-JAB-转基因小鼠的STAT3激活和更严重的结肠炎。这些数据表明，STAT3的过度激活会导致严重的结肠炎，而CIS3通过下调STAT3活性在急性肠炎中起负调节作用。较少的