Thyroid hormone metabolism in the hematopoietic system
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Thyroid hormones are iodinated compounds that are critical to differentiation, apoptosis, and cellular processes in virtually every vertebrate cell. The thyroid gland produces mostly thyroxine (T4) and also 3',3,5-triiodothyronine (T3). T4 acts as a "prehormone" and is converted in the periphery into the more physiologically active T3 via deiodination. Deiodination is also the process by which thyroid hormones are inactivated and thyroid hormone balance is maintained. Types 1 (Dl) and 2 (D2) deiodinase activate T4 into T3. Conversely, inactivation is accomplished by type 3 iodothyronine deiodinase (D3), which is the primary inactivator of both T4 and T3. D3 is highly expressed in fetal tissues and is re-expressed in adult tissues during pathophysiological states. This reactivated D3 leads to local inactivation of thyroid hormones, which is maladaptive in certain situations but may be adaptive in others. We hypothesize that D3 deficiency in hematopoietic cells will affect blood cell function and/or production during inflammatory stress, infection, and anemia. Methods: Human blood cell lines were stimulated with a tumor promoter and ionophore and assayed for deiodinase activity. Conditional knockout mice with blood-cell-specific D3 def1ciency were generated. Their complete blood counts and thyroid function tests were studied to determine the correlation between D3 and the hematopoietic system in both the well state and eventually stress states. Results: Dl, D2 and D3 were not stimulated by stressors in vitro. D3 was successfully knocked out of the hematopoietic system in mice. Blood-cell-specific D3 deficient mice had blood cell counts that were not significantly different from that of mice with a functional enzyme in the normal state (baseline). Mice of both genotypes were euthyroid in the normal state. Conclusion: D3 deficiency in the hematopoietic system was not sufficient to induce pancytopenia or thyroid hormone derangement in the normal state. Future studies will investigate the possible role of D1 and/or D2 in compensating for D3 deficiency. The development of a conditional D3 knockout in blood will provide a useful tool for studying the effect of D3 on blood function and/or development in inflammation, infection, and anemia in future studies.
Thesis (M.A.)--Boston University
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