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Tumor Necrosis Factor, Ceramide, Transforming Growth Factor-ß₁, and Aging Reduce Na⁺/I^- Symporter Messenger Ribonucleic Acid Levels in FRTL-5 Cells¹

Endocrinology Research Laboratory, West Los Angeles VA Medical Center, University of California, Los Angeles, California 90073

Address all correspondence and requests for reprints to: Dr. Jerome M. Hershman, West Los Angeles VA Medical Center, Endocrinology 111D, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: jhershman{at}ucla.edu

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)-ß₁ 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-ß₁, 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 t_1/2 = 0.62 days, a cycloheximide inhibitable effect. Similar treatments with TGF-ß₁, 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-ß₁ 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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