Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta 1) inhibit the expression and activity of Na+/K(+)-ATPase in FRTL-5 rat thyroid cells.
We recently reported that tumor necrosis factor-alpha (TNF-alpha) induction of the synthesis and secretion of transforming growth factor (TGF)-beta 1 by FRTL-5 cells is a thyroid-stimulating hormone (TSH)-dependent and age-dependent process. TNF-alpha is only cytotoxic to aged (> 40 passages) FRTL-5 cells grown in TSH-containing medium, whereas TGF-beta induces programmed cell death (apoptosis) in epithelial cells but not in FRTL-5 cells, which otherwise retain many properties of normal thyroid follicular cells. This cell line is, therefore, a convenient model for studies on the TSH-dependent and age-dependent inhibitory effects of these cytokines on epithelial cell growth, viability, and function. One prominent effect of TNF-alpha (and TGF-beta 1) on FRTL-5 cell function is suppression of iodide uptake, which is markedly stimulated by TSH. In aged FRTL-5 cells, iodide uptake is only about 10% that of young control cells. Na+/K(+)-ATPase activity, which drives iodide uptake by thyroid cells, is inhibited by TNF-alpha and TGF-beta. The following experiments quantitate the effects of TSH, aging, TNF-alpha, and TGF-beta 1 on the expression and activity of Na+/K(+)-ATPase activity in FRTL-5 cells. Young (< 20 passages) and aged (> 40 passages) FRTL-5 cells were treated with various doses (0-100 ng/ml) of recombinant human TNF-alpha or TGF-beta 1 for various times (0-3 days) with and without 2 U/liter TSH. These treatments reduced the rate-limiting Na+/K(+)-ATPase beta 1 mRNA level and Na+/K(+)-ATPase activity in parallel in a dose-dependent and time-dependent fashion. Aged FRTL-5 cells were more sensitive to the inhibitory effects of TNF-alpha, whereas young cells were more sensitive to the suppressive effects of TGF-beta 1 on the expression and activity of Na+/K(+)-ATPase. We conclude that inhibition of Na+/K(+)-ATPase activity by TNF-alpha and TGF-beta in FRTL-5 cells is differentially affected by aging and that this inhibitory effect can be dissociated from effects on cell viability.
Pekary
A E
AE
Endocrinology Research and Diabetes Research Laboratory, West Los Angeles VA Medical Center, CA 90073, USA.
Levin
S R
SR
Johnson
D G
DG
Berg
L
L
Hershman
J M
JM
D000375:Aging / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D006801:Humans; D007454:Iodides / Q000493:pharmacokinetics; D010978:Platelet Factor 4 / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013972:Thyrotropin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007454:Iodides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D010978:Platelet Factor 4; D013972:Thyrotropin; D004247:DNA; D000254:Sodium-Potassium-Exchanging ATPase