title: Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity.
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 (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 MIFT(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.
authors.affiliation: Centers for Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA. yalabed@nshs.edu
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Christine N
authors.initials: CN
authors.lastname: Metz
authors.forename: Kai Fan
authors.initials: KF
authors.lastname: Cheng
authors.forename: Bayan
authors.initials: B
authors.lastname: Aljabari
authors.forename: Sonya
authors.initials: S
authors.lastname: VanPatten
authors.forename: Steven
authors.initials: S
authors.lastname: Blau
authors.forename: Hans
authors.initials: H
authors.lastname: Lee
authors.forename: Mahendar
authors.initials: M
authors.lastname: Ochani
authors.forename: Valentin A
authors.initials: VA
authors.lastname: Pavlov
authors.forename: Thomas
authors.initials: T
authors.lastname: Coleman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Meurice
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
mesh_terms: D000818:Animals; D001665:Binding Sites; D006801:Humans; D007249:Inflammation; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D018805:Sepsis / Q000097:blood / Q000188:drug therapy; D015996:Survival Rate; D013963:Thyroid Hormones / Q000097:blood; D013974:Thyroxine / Q000097:blood / Q000502:physiology* / Q000627:therapeutic use
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D013963:Thyroid Hormones; D013974:Thyroxine