TUMOR-NECROSIS-FACTOR, CERAMIDE, TRANSFORMING GROWTH FACTOR-BETA(1), AND AGING REDUCE NA+ I- SYMPORTER MESSENGER-RIBONUCLEIC-ACID LEVELS INFRTL-5 CELLS/

Iodide uptake, which is necessary for thyroid hormone synthesis, can b e inhibited by aging, withdrawal of TSH, or increased tumor necrosis f actor (TNF) and transforming growth factor (TGF)-beta(1) levels result ing from the nonthyroid illness syndrome. TNF induces receptor-mediate d activation of sphingomyelinase, which converts sphingomyelin to cera mide, a mediator of TNF actions. Thyroid follicular cells transport io dide from blood into the follicular lumen against an iodide gradient b y means of coupled transport of Na+ ions and I- ions via the Na+/I- sy mporter (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 cytok ines regulate I- uptake by thyroid cells. Young (<20 passages) and age d (>40 passages) FRTL-5 cells grown with or without TSH were treated w ith various concentrations of TNF, TGF-beta(1) sphingomyelinase, or ce ramide. NIS messenger RNA (mRNA) levels in aged cells were only 2% of those in young cells. Withdrawal of TSH from young cells reduced NIS m RNA levels by more than 90%. TNF reduced NIS mRNA levels in young cell s grown with TSH at t(1/2) = 0.62 days, a cycloheximide inhibitable ef fect. Similar treatments with TGF-beta(1), sphingomyelinase, or cerami de reduced NIS mRNA by 70-90%. Ceramide reduced I-125(-)-uptake by 50% . The addition of TNF increased both the sphingomyelin and ceramide le vels 3- to 5-fold in young and old cells. We conclude that 1) the decl ine in iodide uptake due to aging, a fall in serum TSH or an increase in TNF or TGF-beta(1) is mediated primarily by a reduction in thyroid NIS expression; and 2) that receptor-mediated activation of sphingomye linase is an important, protein synthesis-dependent, intracellular pat hway for inhibition of NIS expression by TNF.