A new study published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) suggests that thyroxine (T4) is a strong endogenous inhibitor of the migration inhibitory factor (MIF) pro-inflammatory activities. Importantly, the study also indicates that low T4 and high MIF levels may contribute to the lethal systemic inflammatory response during severe sepsis.
Low circulating thyroid hormone levels are common in critically ill patients with severe infections and about 60% of these patients have abnormally low plasma T4 levels, with the lowest levels being observed in patients with sepsis.
The mechanism behind this phenomenon, often referred to as “euthyroid sick syndrome” remain poorly understood.
Migration inhibitory factor is a cytokine involved in cell-mediated immunity, immunoregulation, inflammation, and is also known to be induced by glucocorticoids, and being able to override their anti-inflammatory actions.
Migration inhibitory factor is implicated in the pathogenesis of systemic infections, autoimmune diseases, cancer, metabolic disorders and atherosclerosis. Of note, plasma MIF levels are significantly elevated in non-survivors of severe sepsis, compared with survivors, and administration of antibodies against MIF improves survival in experimental sepsis.
In the PNAS study, Yousef Al-Abed and colleagues from the Feinstein Institute for Medical Research, Manhasset, NY, USA, provide evidence for an inverse correlation between plasma T4 and MIF levels during the progression of sepsis, and identify T4 as a potential endogenous antagonist of MIF inflammatory activity.
According to the authors the low plasma free T4 levels “could result from a significant endogenous T4 fraction binding the hydrophobic pocket within the MIF molecule”. As during sepsis, plasma MIF levels can reach high levels, “this binding may not be sufficient to effectively inhibit MIF pro-inflammatory activity and prevent an overwhelming inflammatory response”.
These findings indicate a previously unrecognized but clinically relevant interaction between T4 and MIF, two key molecules in the critically ill patient with severe infections.
SOURCE: Proc Natl Acad Sci USA 2011, 108:8224. Epub 2011 May 2