TY - JOUR
T1 - Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity
AU - Al-Abed, Yousef
AU - Metz, Christine N.
AU - Cheng, Kai Fan
AU - Aljabari, Bayan
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.
PY - 2011/5/17
Y1 - 2011/5/17
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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U2 - 10.1073/pnas.1017624108
DO - 10.1073/pnas.1017624108
M3 - Article
C2 - 21536912
AN - SCOPUS:79957742886
SN - 0027-8424
VL - 108
SP - 8224
EP - 8227
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -