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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human genetic deficiencies reveal the roles of complement in the inflammatory network: Lessons from nature
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Human genetic deficiencies reveal the roles of complement in the inflammatory network: Lessons from nature

机译:人类遗传缺陷揭示补体在炎症网络中的作用:自然的教训

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摘要

Complement component C5 is crucial for experimental animal inflammatory tissue damage; however, its involvement in human inflammation is incompletely understood. The responses to Gram-negative bacteria were here studied taking advantage of human genetic complement-deficiencies-nature's own knockouts-including a previously un-described C5 defect. Such deficiencies provide a unique tool for investigating the biological role of proteins. The experimental conditions allowed cross-talk between the different inflammatory pathways using a whole blood model based on the anticoagulant lepirudin, which does not interfere with the complement system. Expression of tissue factor, cell adhesion molecules, and oxidative burst depended highly on C5, mediated through the activation product C5a, whereas granulocyte enzyme release relied mainly on C3 and was C5a-independent. Release of cytokines and chemokines was mediated to varying degrees by complement and CD14; for example, interleukin (IL)-1β and IL-8 were more dependent on complement than IFN-γ and IL-6, which were highly dependent on CD14. IL-1 receptor antagonist (IL-1ra) and IFN-γ inducible protein 10 (IP-10) were fully dependent on CD14 and inversely regulated by complement, that is, complement deficiency and complement inhibition enhanced their release. Granulocyte responses were mainly complement-dependent, whereas monocyte responses were more dependent on C014. Notably, all responses were abolished by combined neutralization of complement and CD14. The present study provides important insight into the comprehensive role of complement in human inflammatory responses to Gram-negative bacteria.
机译:补体成分C5对实验动物的炎症组织损伤至关重要。然而,其与人类炎症的关系尚不完全清楚。本文利用人类遗传补体缺陷-自然自身的基因敲除(包括先前未描述的C5缺陷)研究了对革兰氏阴性细菌的反应。这种缺陷为研究蛋白质的生物学作用提供了独特的工具。实验条件允许使用基于抗凝肽芦丁的全血模型在不同的炎症途径之间进行串扰,而不会干扰补体系统。组织因子,细胞粘附分子和氧化爆发的表达高度依赖于C5,并通过活化产物C5a介导,而粒细胞酶的释放主要依赖于C3,并且不依赖于C5a。补体和CD14介导不同程度的细胞因子和趋化因子释放。例如,白介素(IL)-1β和IL-8比IFN-γ和IL-6更依赖补体,而IFN-γ和IL-6高度依赖CD14。 IL-1受体拮抗剂(IL-1ra)和IFN-γ诱导蛋白10(IP-10)完全依赖CD14,并由补体反向调节,即补体缺乏和补体抑制增强了它们的释放。粒细胞应答主要依赖补体,而单核细胞应答更依赖于C014。值得注意的是,补体和CD14的联合中和作用消除了所有反应。本研究为补体在人类对革兰氏阴性细菌的炎症反应中的全面作用提供了重要的见识。

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    Departments of Medicine, Nordland Hospital, Bodo, and University of Tromso, Norway;

    Laboratory Medicine, Nordland Hospital, Bodo, and University of Tromso, Norway;

    Institute of Immunology, Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Norway;

    Institute of Immunology, Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Norway;

    Institute of Immunology, Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Norway;

    Institute of Immunology, Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Norway;

    Anaesthesia and Intensive Care, Nordland Hospital, Bodo, and University of Tromso, Norway;

    Laboratory Medicine, Nordland Hospital, Bodo, and University of Tromso, Norway;

    Forde Hospital, Forde, Norway, Norwegian Institute of Public Health, Oslo, Norway;

    Department of Pediatrics, Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Norway;

    Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway;

    Department of Clinical Immunology. Section 7631, Rigshospitalet, University of Copenhagen, Denmark;

    Department of Clinical Immunology. Section 7631, Rigshospitalet, University of Copenhagen, Denmark;

    Laboratory of Protein Chemistry, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA;

    Institute of Immunology, Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Norway;

    Laboratory Medicine, Nordland Hospital, Bodo, and University of Tromso, Norway Institute of Immunology, Rikshospitalet University Hospital and Faculty of Medicine, University of Oslo, Norway;

  • 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);
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