Metabolism of L-thyroxine by phagocytosing human leukocytes

Abstract

Intact normal human leukocytes deiodinated L-thyroxine (T(4)) with the generation of inorganic iodide, chromatographically immobile origin material, and small quantities of L-triiodothyronine (T(3)). When phagocytosis was induced in the leukocytes through the addition of zymosan particles that had been opsonized by coating with plasma, T(4)-deiodination was greatly stimulated. In addition to the stimulation of T(4)-deiodination, the accumulation by the leukocytes of undegraded T(4) was increased. Anoxia, which has previously been shown not to interfere with phagocytosis, did not prevent the increased cellular accumulation of T(4) that phagocytosis induced, but virtually abolished T(4)-deiodination. On the other hand, calcium, which has previously been shown to be required for optimal phagocytosis, was required for the increase in both the cellular accumulation and deiodination of T(4) that phagocytosis induced. Phospholipase-C, which has previously been shown to induce a metabolic burst that mimics that induced by phagocytosis, did not increase the cellular accumulation or deiodination of T(4). On the other hand, colchicine, which has previously been shown to depress the metabolic burst that accompanies phagocytosis, did not prevent the increase in either the cellular accumulation or deiodination of T(4) that phagocytosis induced. Thus, increased accumulation of T(4) by the leukocytes during phagocytosis appears to be the primary factor responsible for the stimulation of deiodination that phagocytosis induces. The increased accumulation of T(4) did not appear to be owing to engulfment of suspending medium surrounding the particles or to binding of T(4) to the particles themselves. In addition to the enhanced cellular accumulation, other factors related to the metabolic burst that accompanies phagocytosis might also be involved in the stimulation of T(4)-deiodination. In leukocytes from two patients with chronic granulomatous disease, a disorder in which phagocytosis appears to occur normally but in which the metabolic burst and attendant increase in hydrogen peroxide generation do not occur, stimulation of T(4)-deiodination was either greatly diminished or totally lacking. In myeloperoxidase-deficient leukocytes, on the other hand, stimulation of T(4)-deiodination was at least as great as that in normal cells. Thus, we conclude that the primary factor responsible for the increased deiodination of T(4) that phagocytosis induces is the enhanced cellular uptake of hormone. The increased generation of hydrogen peroxide that accompanies phagocytosis may be necessary for the enhanced deiodination of the accumulated T(4), but the latter reaction does not require the mediation of myeloperoxidase.