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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis
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Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

机译：LPS诱导的TNF-α因子（LITAF）的全身删除显着改善了实验性内毒素性休克和炎症性关节炎

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摘要

LPS-induced TNF-α factor (LITAF) mediates cytokine expression in response to endotoxin challenge. Previously, we reported that mac-rophage-specific LITAF-deficient (macLITAF~(-/-)) mice exposed to LPS have a delayed onset in the serum levels of proinflammatory cyto-kines and prolonged persistence of anti-inflammatory cytokines, but only partial protection from endotoxic shock. We postulated that greater protection might be achieved if LITAF were deleted from all LITAF-producing cells, including macrophages. Using a Cre-loxP system, we engineered a tamoxifen-induced recombination mouse [tamLrrAF(i)~(-/-)] that resulted in whole-body LITAF deficiency. Our findings demonstrate that (/) tamLITAF(i)~(-/-) mice are more resistant to systemic Escherichia coli LPS-induced lethality than our previous macLITAF~(-/-) mice, providing evidence that LITAF-producing cells other than LysMCre-positive cells play an important role in mediating endotoxic shock; (ii) tamLITAF(i)~(-/-) mice show a similar pattern of cytokine expression with decreased proinflammatory and prolonged anti-inflammatory mediators compared with WT mice; and (iii) tamLITAF(i)~(-/-) mice, compared with WT mice, display a significant reduction in bone resorption and inflammation associated with a local chronic inflammatory disease-namely, collagen antibody-induced arthritis. Our findings offer a unique model to study the role of LITAF in systemic and chronic local inflammatory processes, and pave the way for anti-LITAF therapeutic approaches for the treatment of TNF-mediated inflammatory diseases.
机译：LPS诱导的TNF-α因子（LITAF）介导细胞因子对内毒素激发的表达。以前，我们报道了暴露于LPS的缺乏巨噬细胞特异性LITAF的小鼠（macLITAF〜（-/-））在血清中的促炎细胞因子水平起病和延缓了消炎细胞因子的持续存在，但仅免受内毒素性休克的部分保护。我们假设，如果从所有产生LITAF的细胞（包括巨噬细胞）中删除LITAF，可能会获得更大的保护。使用Cre-loxP系统，我们设计了他莫昔芬诱导的重组小鼠[tamLrrAF（i）〜（-/-）]，该小鼠导致全身LITAF缺乏。我们的发现表明（/）tamLITAF（i）〜（-/-）小鼠比我们以前的macLITAF〜（-/-）小鼠对系统性大肠杆菌LPS致死性具有更强的抵抗力，这提供了除LITAF产生细胞以外的其他细胞的证据。 LysMCre阳性细胞在介导内毒素休克中起重要作用。 （ii）与野生型小鼠相比，tamLITAF（i）〜（-/-）小鼠表现出相似的细胞因子表达模式，具有降低的促炎介质和延长的抗炎介质。 （iii）与野生型小鼠相比，tamLITAF（i）〜（-/-）小鼠显示出与局部慢性炎性疾病（即胶原抗体诱导的关节炎）相关的骨吸收和炎症显着降低。我们的发现为研究LITAF在系统性和慢性局部炎症过程中的作用提供了独特的模型，并为抗LITAF治疗方法治疗TNF介导的炎症性疾病铺平了道路。

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  • 作者

    Jamie C. Merrill; Jian You; Cara Constable; Susan E. Leeman; Salomon Amar;

  • 作者单位

    Center for Anti-Inflammatory Therapeutics, Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, MA 02118;

    Center for Anti-Inflammatory Therapeutics, Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, MA 02118;

    Center for Anti-Inflammatory Therapeutics, Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, MA 02118;

    Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118;

    Center for Anti-Inflammatory Therapeutics, Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, MA 02118;

  • 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
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  • 关键词

    septic shock; multiplex;

    机译：败血性休克;多重;

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