title: Attenuation of thyroid hormone action by 1,25-dihydroxyvitamin D3 in pituitary cells.
abstract: Interactions between thyroid hormone and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] were examined in a rat pituitary tumor cell line, GH4C1. Cells were incubated in thyroid hormone-depleted medium for 2 days, and specific nuclear binding of [125I]T3 was measured. 1,25-(OH)2D3 decreased nuclear [125I]T3 binding without changing total cellular uptake of [125I]T3. This 1,25-(OH)2D3 effect required 2-3 h to become evident and 24 h to reach a maximum (40-50% of control) and was reversible. Treatment with 1,25-(OH)2D3 for 8 h changed the maximal binding capacity for [125I]T3 from 80.2 +/- 2.9 to 50.3 +/- 6.3 fmol/10(6) cells, whereas Kd was not significantly altered. The decrease in [125I]T3 binding was dose dependent, with an IC50 for 1,25-(OH)2D3 of 1 nM in thyroid hormone-depleted medium. 1,25-(OH)2D3 caused little change in [125I]T3 binding to isolated nuclei, i.e. 1,25-(OH)2D3 does not compete directly with [125I]T3 for binding. It is unlikely that 1,25-(OH)2D3 decreased [125I]T3 binding by increasing the concentration of intracellular free calcium ([Ca2+]i), since 1,25-(OH)2D3 did not change [Ca2+]i in Indo-I-loaded GH4C1 cells. Two major species (6 and 2.6 kilobases) of mRNA for c-erb-A, which have been reported to encode nuclear thyroid hormone receptors, were found by Northern blot analysis, and both were decreased by treatment with 1,25-(OH)2D3 for 8 h. T3 (2 nM) caused a 3-fold increase in GH production over 72 h and 1,25-(OH)2D3 inhibited GH induction by T3, with an IC50 at approximately 1 nM. 1,25-(OH)2D3 stimulated PRL synthesis 5-fold when 10 nM T3 was present, but not when T3 was absent. In summary, 1,25-(OH)2D3 caused a dose-dependent down-regulation of nuclear thyroid hormone receptors at a pretranslational level and diminished GH induction by T3. These results suggest that 1,25-(OH)2D3 inhibits GH synthesis indirectly, at least partly, by attenuating endogenous thyroid hormone action.
authors: Department of Pharmacology, University of Rochester School of Medicine, New York 14642.
authors: H
authors: H
authors: Kaji
authors: P M
authors: PM
authors: Hinkle
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D013006:Growth Hormone / Q000096:biosynthesis; D007700:Kinetics; D010911:Pituitary Neoplasms; D011061:Poly A / Q000235:genetics / Q000302:isolation & purification; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D011061:Poly A; D012313:RNA; D013006:Growth Hormone; D002117:Calcitriol; D002118:Calcium