Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity

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

Research output: Contribution to journalArticle

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Abstract

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 (T4) 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 T4 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-T4 (or its hormonally inert isomer D-T4) significantly, and dose-dependently, inhibited the catalytic activity of this pocket. Moreover, administration of exogenous D-T4 significantly improved survival in mice with severe sepsis. To examine the specificity of the MIF:T4 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-T4 significantly inhibited leukocyte infiltration in wild-type mice but not in MIF knockout mice, providing evidence that in vivo T4 may influence MIF-mediated inflammatory responses via inhibition of its hydrophobic proinflammatory pocket. These findings demonstrate a new physiological role for T4 as a natural inhibitor of MIF proinflammatory activity. The data may also, in part, explain the low plasma T4 concentrations in critically ill, euthyroid patients and suggest that targeting the imbalance between MIF and T4 may be beneficial in improving outcome from sepsis.

Original languageEnglish (US)
Pages (from-to)8224-8227
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number20
DOIs
StatePublished - May 17 2011
Externally publishedYes

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Macrophage Migration-Inhibitory Factors
Thyroxine
Sepsis
Knockout Mice
Euthyroid Sick Syndromes
Carrageenan
Thyroid Hormones
Critical Illness
Rodentia
Leukocytes
Air
Cytokines
Inflammation
Survival

ASJC Scopus subject areas

  • General

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Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity. / Al-Abed, Yousef; Metz, Christine N.; Cheng, Kai Fan; Aljabari, Bayan; VanPatten, Sonya; Blau, Steven; Lee, Hans; Ochani, Mahendar; Pavlov, Valentin A.; Coleman, Thomas; Meurice, Nathalie; Tracey, Kevin J.; Miller, Edmund J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 20, 17.05.2011, p. 8224-8227.

Research output: Contribution to journalArticle

Al-Abed, Y, Metz, CN, Cheng, KF, Aljabari, B, VanPatten, S, Blau, S, Lee, H, Ochani, M, Pavlov, VA, Coleman, T, Meurice, N, Tracey, KJ & Miller, EJ 2011, 'Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 20, pp. 8224-8227. https://doi.org/10.1073/pnas.1017624108
Al-Abed, Yousef ; Metz, Christine N. ; Cheng, Kai Fan ; Aljabari, Bayan ; VanPatten, Sonya ; Blau, Steven ; Lee, Hans ; Ochani, Mahendar ; Pavlov, Valentin A. ; Coleman, Thomas ; Meurice, Nathalie ; Tracey, Kevin J. ; Miller, Edmund J. / Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 20. pp. 8224-8227.
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AU - VanPatten, Sonya

AU - Blau, Steven

AU - Lee, Hans

AU - Ochani, Mahendar

AU - Pavlov, Valentin A.

AU - Coleman, Thomas

AU - Meurice, Nathalie

AU - Tracey, Kevin J.

AU - Miller, Edmund J.

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N2 - 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 (T4) 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 T4 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-T4 (or its hormonally inert isomer D-T4) significantly, and dose-dependently, inhibited the catalytic activity of this pocket. Moreover, administration of exogenous D-T4 significantly improved survival in mice with severe sepsis. To examine the specificity of the MIF:T4 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-T4 significantly inhibited leukocyte infiltration in wild-type mice but not in MIF knockout mice, providing evidence that in vivo T4 may influence MIF-mediated inflammatory responses via inhibition of its hydrophobic proinflammatory pocket. These findings demonstrate a new physiological role for T4 as a natural inhibitor of MIF proinflammatory activity. The data may also, in part, explain the low plasma T4 concentrations in critically ill, euthyroid patients and suggest that targeting the imbalance between MIF and T4 may be beneficial in improving outcome from sepsis.

AB - 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 (T4) 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 T4 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-T4 (or its hormonally inert isomer D-T4) significantly, and dose-dependently, inhibited the catalytic activity of this pocket. Moreover, administration of exogenous D-T4 significantly improved survival in mice with severe sepsis. To examine the specificity of the MIF:T4 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-T4 significantly inhibited leukocyte infiltration in wild-type mice but not in MIF knockout mice, providing evidence that in vivo T4 may influence MIF-mediated inflammatory responses via inhibition of its hydrophobic proinflammatory pocket. These findings demonstrate a new physiological role for T4 as a natural inhibitor of MIF proinflammatory activity. The data may also, in part, explain the low plasma T4 concentrations in critically ill, euthyroid patients and suggest that targeting the imbalance between MIF and T4 may be beneficial in improving outcome from sepsis.

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