Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity
Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity
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DOI：
10.1073/pnas.1017624108
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发表时间：
2011-05-17
影响因子：
11.1
通讯作者：
Miller, Edmund J.
中科院分区：
文献类型：
--
作者：
Al-Abed, Yousef;Metz, Christine N.;Miller, Edmund J.
脓毒症期间甲状腺激素血浆浓度异常低通常发生在没有甲状腺疾病的情况下；然而，人们对“甲状腺功能正常病态综合征”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））和促炎细胞因子巨噬细胞迁移抑制因子（MIF）之间以前未被认识的相互作用，及其在脓毒症中的临床相关性。我们发现，在严重败血症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 分子含有一个疏水性口袋，这对于其许多促炎活性非常重要。 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该口袋的催化活性。此外，外源性D-T(4)的施用显着提高了患有严重脓毒症的小鼠的存活率。为了检查 MIF: T(4) 相互作用的特异性，将野生型和 MIF 敲除小鼠置于角叉菜胶-气囊炎症模型中，然后用 D-T(4) 或载体进行治疗。 D-T(4) 显着抑制野生型小鼠的白细胞浸润，但不抑制 MIF 敲除小鼠的白细胞浸润，这提供了体内 T(4) 可能通过抑制其疏水性促炎口袋来影响 MIF 介导的炎症反应的证据。这些发现证明了 T(4) 作为 MIF 促炎活性的天然抑制剂的新生理作用。这些数据还可能部分解释了甲状腺功能正常的重症患者血浆 T(4) 浓度较低的原因，并表明针对 MIF 和 T(4) 之间的不平衡可能有利于改善脓毒症的预后。
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.