A Characteristic Serpin Cleavage Product of Thyroxine-Binding Globulin Appears in Sepsis Sera

Abstract

T4-binding globulin (TBG), the principal thyroid hormone-binding protein of serum, is a member of the serine protease inhibitor (serpin) superfamily. We report a characteristic serpin cleavage product of TBG in sepsis sera. At 49-50 kDa, the TBG remnant is 4-5 kDa smaller than the intact protein and is the same molecular mass as a TBG cleavage product produced by incubation with polymorphonuclear elastase. Incubation with polymorphonuclear leukocytes also produces the 49- to 50-kDa remnant, and this proteolysis is stimulated by zymosan activation. Polymorphonuclear cell cleavage of TBG increases the ratio of free/bound T4. As previously described, in vitro cleavage of TBG by elastase also increases free/bound T4. These findings are consistent with the hypothesis that serine proteases present at inflammatory sites cleave TBG, releasing its hormonal ligands.

Thyroid hormone metabolism in innate immune cells

“…THs are drawn to the site of bacterial infection (Adelberg et al 1971). Activated phagocytosing neutrophils are capable of cleavage of thyroxinebinding globulin (TBG), thus increasing the amount of extracellularly available T 4 (Jirasakuldech et al 2000). As mentioned previously, phagocytosing neutrophils also metabolize significant amounts of TH (Woeber 1971, Woeber et al 1972, Klebanoff & Green 1973, Woeber & Ingbar 1973.…”

Structural mechanism for the carriage and release of thyroxine in the blood

“…In particular, TBG undergoes the profound and irreversible conformational change on cleavage of its reactive loop, which is characteristic of the serpins (5,6). Such cleavage of the reactive loop of TBG by proteases does occur during sepsis to give a 3-fold reduction in its binding affinity (7)(8)(9). However, because only a minor proportion, Ͻ20%, of the circulating TBG is bound to thyroxine, even this relatively small decrease in affinity will result in an effective release of thyroxine (10), as demonstrably occurs at sites of inf lammation (11).…”

Structural basis of albumin–thyroxine interactions and familial dysalbuminemic hyperthyroxinemia

“…Thyroxine-binding globulin, which has the highest affinity for T 4 (K d ϭ 0.1 nM), binds about three-quarters of the hormone carried in the circulation; the remainder is divided more or less equally between transthyretin and HSA. Thyroxine binding globulin appears to be adapted to target the hormone to sites of inflammation because its affinity for T 4 is reduced on cleavage by neutrophil elastase (2)(3)(4). Albumin binds T 4 with a K d of Ϸ2 M and provides an important fast-response reservoir for the hormone during capillary transit (4).…”