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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus
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Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

机译:NOD Idd3基因座中IL-2和IL-21之间的奇偶性丧失

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摘要

IL-2 and IL-21 are two cytokines with great potential to affect autoimmune infiltration of nonlymphoid tissue, and are contained within the strongest non-MHC-linked locus for type 1 diabetes (T1D) susceptibility on the nonobese diabetic (NOD) mouse (Idd3). IL-21 is necessary for the development of diabetes in the NOD mouse, but a number of important studies argue that decreased expression of IL-2 explains Idd3. In this study, we demonstrate that the amount of IL-21, but not IL-2, correlated with T1D incidence. During our analyses of the IL-2/IL-21 interval, we found that mice segregate into one of two distinct expression profiles. In the first group, which includes the C57BL/6 strain, both Il2 and Il21 were expressed at low levels. In the other group, which includes the NOD strain, Il2 and Il21 were both highly expressed. However, because NOD IL-2 mRNA was relatively unstable, IL-2 production was remarkably similar between strains. The increased production of IL-21 in NOD mice was found to result from two single nucleotide polymorphisms within the distal promoter region that conferred increased binding affinity for the transcription factor Sp1. Our findings indicate that a loss of locus parity after decreased IL-2 mRNA stability ensures that the high-expressing IL-21 allele persists in nature and provides a basis for autoimmunity.
机译:IL-2和IL-21是两种有潜力影响非淋巴组织自身免疫浸润的细胞因子,它们被包含在非肥胖型糖尿病(NOD)小鼠对1型糖尿病(T1D)易感性最强的非MHC连锁基因位点( Idd3)。 IL-21是NOD小鼠糖尿病发展所必需的,但是许多重要研究认为,IL-2的表达降低解释了Idd3。在这项研究中,我们证明IL-21的含量与T1D发病率相关,而与IL-2无关。在我们对IL-2 / IL-21间隔的分析中,我们发现小鼠分离成两种不同的表达谱之一。在包括C57BL / 6菌株的第一组中,II2和Il21均以低水平表达。在包括NOD菌株的另一组中,Il2和Il21均高表达。但是,由于NOD IL-2 mRNA相对不稳定,因此菌株之间IL-2的产生非常相似。发现在NOD小鼠中IL-21的产量增加是由于远端启动子区域内的两个单核苷酸多态性导致的,该两个多态性赋予了对转录因子Sp1的增加的结合亲和力。我们的发现表明,IL-2 mRNA稳定性降低后,基因座平价的丧失确保了高表达的IL-21等位基因在自然界中持续存在,并为自身免疫提供了基础。

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  • 作者单位

    Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia University of New South Wales, School of Biotechnology and Biomolecular Sciences, UNSW, Sydney 2052, Australia;

    Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia;

    Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Sciences, Barts/Queen Mary's School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, United Kingdom School of Life Sciences, Kingston University, Surrey KT1 1LQ, United Kingdom;

    Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, F59, S-141 86 Stockholm, Sweden;

    Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia St. Vincent's Clinical School, University of NSW, Sydney, NSW, Sydney, NSW, Australia and WCU-IBB Program, POSTECH, Korea St. Vincent's Clinical School, University of NSW, Sydney, NSW 2010, Australia;

    Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia St. Vincent's Clinical School, University of NSW, Sydney, NSW 2010, Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    type 1 diabetes; cytokines; transcription factor; allele; promoter;

    机译:1型糖尿病;细胞因子转录因子等位基因发起人;

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