Degradation of Thyroid Hormones by Phagocytosing Human Leukocytes

Abstract

A B S T R A CT Thyroxine (T4) and triiodothyronine (T3) are rapidly degraded by a purified preparation of myeloperoxidase (MPO) and H202 with the formation of iodide and material which remains at the origin on paper chromatography. Deiodination by MPO and H202 occurs more readily at pH 7.0 than at pH 5.0 in contrast to iodination by this system which is known to occur more readily at pH 5.0 than at pH 7.0. Degradation is inhibited by azide, cyanide, ascorbic acid, and propylthiouracil. Methimazole stimulates deiodination by MI PO and H202 but inhibits this reaction when MIPO is replaced by lactoperoxidase or horseradish peroxidase.Intact human leukocytes, in the resting state, degrade T4 and T3 slowly; degradation, however, is increased markedly during phagocytosis of preopsonized particles. Serum inhibits this reaction. T3 can be detected as a minor product of T4 degradation. Proteolytic digestion of the reaction products increases the recovery of monoiodotyrosine. The fixation of iodine in the cytoplasm of leukocytes which contain ingested bacteria was detected radioautographically. Chronic granulomatous disease leukocytes, which are deficient in H202 formation, degrade T4 and T3 poorly during phagocytosis. MPO-deficient leukocytes degrade the thyroid hormones at a slower rate than do normal leukocytes although considerable degradation is still observed. Azide, cyanide, ascorbic acid, and propylthiouracil which inhibit certain peroxidasecatalyzed reactions inhibit degradation by normal leukocytes; however, inhibition is incomplete. Formation of iodinated origin material is inhibited to a greater degree by azide, cyanide, and propylthiouracil than is deiodination. Methimazole inhibits the formation of iodinated origin material by both normal and MPO-deficient leukoThese studies were presented in part at the 64th These data suggest that both MPO-dependent and MPO-independent systems are involved in the degradation of T4 and T3 by phagocytosing leukocytes. The role of leukocytic degradation of T4 and T3 in thyroid hormone economy and in leukocytic microbicidal activity is considered.

Nongenomic effect of thyroid hormone on free-radical production in human polymorphonuclear leukocytes

“…The presumed mechanism was the conversion of T 4 to T 3 by PMNLs, freeing up iodide to kill micro-organisms (Klebanoff & Green 1973). Considering our results, that PTU pre-incubation had no specific effect on T 4 -induced O 2 production, we hypothesized that the source of halide for increased killing might be the thyroid hormone-induced halide incorporation into PMNLs.…”

Thyroid hormone metabolism in innate immune cells

“…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. This suggests that TH metabolism plays an important role in infiltrating neutrophils during infection.…”

“…Murine neutrophils contain the TH transporter MCT8, whereas human neutrophils express MCT10 but not MCT8 mRNA (Boelen et al 2005, van der Spek et al 2016. It has long been known that activated neutrophils are capable of deiodinating both T 3 and T 4 (Woeber 1971, Woeber et al 1972, Klebanoff & Green 1973, Woeber & Ingbar 1973. Research from the seventies already found that phagocytosing human neutrophils can generate both T 3 and rT 3 from T 4 and that this deiodinating activity was mainly present in the granule fraction of the cells (Woeber 1976(Woeber , 1978.…”

“…Most authors find that metabolism of TH by phagocytosing neutrophils results in the production of inorganic iodide, suggesting the involvement of the deiodinase enzymes (Woeber et al 1972, Klebanoff & Green 1973, Woeber & Ingbar 1973. Other authors have found that phagocytosing neutrophils are capable of ether-linked cleavage of T 4 , which results in the formation of diiodotyrosine (DIT) (Burger et al 1983).…”

“…Other authors have found that phagocytosing neutrophils are capable of ether-linked cleavage of T 4 , which results in the formation of diiodotyrosine (DIT) (Burger et al 1983). The degradation of TH requires the intracellular formation of ROS as neutrophils from patients with chronic granulomatous disease, which is characterized by defective NAPDH oxidase resulting in reduced ROS generation, have significantly impaired ability to degrade TH (Klebanoff & Green 1973, Woeber & Ingbar 1973, Burger et al 1983. Although isolated MPO is capable of degrading TH in vitro, neutrophils from MPO-deficient patients degrade TH to the same degree as controls suggesting that the degradation of TH by leukocytes is not MPO dependent in vivo (Klebanoff & Green 1973, Woeber & Ingbar 1973, Burger et al 1983.…”