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Endocrinology. 1998 Feb;139(2):703-12.

Tumor necrosis factor, ceramide, transforming growth factor-beta1, and aging reduce Na+/I- symporter messenger ribonucleic acid levels in FRTL-5 cells.

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  • 1Endocrinology Research Laboratory, West Los Angeles VA Medical Center, University of California, 90073, USA.


Iodide uptake, which is necessary for thyroid hormone synthesis, can be inhibited by aging, withdrawal of TSH, or increased tumor necrosis factor (TNF) and transforming growth factor (TGF)-beta1 levels resulting from the nonthyroid illness syndrome. TNF induces receptor-mediated activation of sphingomyelinase, which converts sphingomyelin to ceramide, a mediator of TNF actions. Thyroid follicular cells transport iodide from blood into the follicular lumen against an iodide gradient by means of coupled transport of Na+ ions and I- ions via the Na+/I- symporter (NIS). An inward Na+ gradient is maintained by Na+/K+-ATPase. The recent cloning and sequencing of the rat NIS complementary DNA has made possible studies on the mechanism by which TSH, aging, and cytokines regulate I- uptake by thyroid cells. Young (<20 passages) and aged (>40 passages) FRTL-5 cells grown with or without TSH were treated with various concentrations of TNF, TGF-beta1, sphingomyelinase, or ceramide. NIS messenger RNA (mRNA) levels in aged cells were only 2% of those in young cells. Withdrawal of TSH from young cells reduced NIS mRNA levels by more than 90%. TNF reduced NIS mRNA levels in young cells grown with TSH at t1/2 = 0.62 days, a cycloheximide inhibitable effect. Similar treatments with TGF-beta1, sphingomyelinase, or ceramide reduced NIS mRNA by 70-90%. Ceramide reduced 125I(-)-uptake by 50%. The addition of TNF increased both the sphingomyelin and ceramide levels 3- to 5-fold in young and old cells. We conclude that 1) the decline in iodide uptake due to aging, a fall in serum TSH or an increase in TNF or TGF-beta1 is mediated primarily by a reduction in thyroid NIS expression; and 2) that receptor-mediated activation of sphingomyelinase is an important, protein synthesis-dependent, intracellular pathway for inhibition of NIS expression by TNF.

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