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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity
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Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity

机译：甲状腺素是巨噬细胞迁移抑制因子（MIF）活性的潜在内源性拮抗剂

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摘要

Abnormally low plasma concentrations of thyroid hormones during sepsis often occur in the absence of thyroidal illness; however, the mechanisms involved in the "euthyroid sick syndrome" remain poorly understood. Here, we describe a previously unrecognized interaction between the thyroid hormone thyroxine (T_4) and the proinflammatory cytokine macrophage migration inhibitory factor (MIF), together with its clinical relevance in sepsis. We found that in both patients with severe sepsis, and our rodent model, low plasma T_4 concentrations were inversely correlated with plasma MIF concentrations. The MIF molecule contains a hydrophobic pocket that is important for many of its proinflammatory activities. Binding of L-T_4 (or its hormonally inert isomer D-T_4) significantly, and dose-dependently, inhibited the catalytic activity of this pocket. Moreover, administration of exogenous D-T_4 significantly improved survival in mice with severe sepsis. To examine the specificity of the MIF:T_4 interaction, wild-type and MIF knockout mice were subjected to the carrageenan-air pouch model of inflammation and then treated with D-T_4 or vehicle. D-T_4 significantly inhibited leukocyte infiltration in wild-type mice but not in MIF knockout mice, providing evidence that in vivo T_4 may influence MIF-mediated inflammatory responses via inhibition of its hydrophobic proinflammatory pocket. These findings demonstrate a new physiological role for T_4 as a natural inhibitor of MIF proinflammatory activity. The data may also, in part, explain the low plasma T_4 concentrations in critically ill, euthyroid patients and suggest that targeting the imbalance between MIF and T_4 may be beneficial in improving outcome from sepsis.
机译：脓毒症期间，甲状腺激素的血浆浓度异常低通常在没有甲状腺疾病的情况下发生。然而，有关“甲状腺疾病综合症”的机制仍知之甚少。在这里，我们描述了甲状腺激素甲状腺素（T_4）和促炎性细胞因子巨噬细胞迁移抑制因子（MIF）之间先前无法识别的相互作用，以及其在脓毒症中的临床意义。我们发现在患有严重败血症的两名患者和我们的啮齿动物模型中，低血浆T_4浓度与血浆MIF浓度呈负相关。 MIF分子包含一个疏水口袋，这对于其许多促炎活性很重要。 L-T_4（或其激素惰性异构体D-T_4）的结合显着且剂量依赖性地抑制了该口袋的催化活性。而且，外源性D-T_4的施用显着改善了患有严重败血症的小鼠的存活。为了检查MIF：T_4相互作用的特异性，对野生型和MIF基因敲除小鼠进行了角叉菜胶气袋炎症模型的治疗，然后用D-T_4或溶媒进行处理。 D-T_4显着抑制野生型小鼠中的白细胞浸润，但不抑制MIF基因敲除小鼠，这提供了体内T_4可能通过抑制其疏水性促炎口袋影响MIF介导的炎症反应的证据。这些发现证明T_4作为MIF促炎活性的天然抑制剂具有新的生理作用。该数据还可以部分解释重症，甲状腺功能正常的患者的血浆T_4浓度低，并提示针对MIF和T_4之间的不平衡可能有助于改善败血症的预后。

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    Yousef Al-Abed; Christine N. Metz; Kai Fan Cheng; Bayan Aljabari; Sonya VanPatten; Steven Blau; Hans Lee; Mahendar Ochani; Valentin A. Pavlov; Thomas Coleman; Nathalie Meurice; Kevin J. Tracey; Edmund J. Miller;

  • 作者单位

    Centers for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    lmmunology and Inflammation The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    Centers for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    Centers for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    Centers for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    Department of Surgery North Shore University Hospital,300 Community Drive, Manhasset, NY 11030;

    Division of Pulmonary Critical Care Medicine, North Shore University Hospital,300 Community Drive, Manhasset, NY 11030;

    Centers for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    Centers for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    Centers for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    Heart and Lung Research, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    Centers for Biomedical Science The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030;

    lmmunology and Inflammation The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030,Division of Pulmonary Critical Care Medicine, North Shore University Hospital,300 Community Drive, Manhasset, NY 11030,Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004;

  • 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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