TNF-ALPHA, TSH, AND AGING REGULATE TGF-BETA SYNTHESIS AND SECRETION IN FRTL-5 RAT-THYROID CELLS

Tumor necrosis factor-alpha (TNF-alpha), a cytokine produced by macrop hages in response to a variety of pathological conditions, can inhibit thyroid cell function in vitro and in vivo. TNF-alpha induction of tr ansforming growth factor-beta 1 (TGF-beta 1) in rat endothelial cells suggested that TGF-beta, a known mediator of inflammatory effects of T NF-alpha may be involved in the sensitivity of aged thyroid cells to T NF-alpha (G. Chen, A. E. Pekary, and J. M. Hershman. Endocrinology 131 : 863-870, 1992). To determine whether TNF-alpha induces TGF-beta prod uction in FRTL-5 cells, young (< 20 passages) and aged (> 40 passages) FRTL-5 cells were grown to near confluency in medium containing 2 U/l of bovine thyroid-stimulating hormone [TSH; B-hormone (6H) medium] or no TSH [5-hormone (5H) medium]. TNF-alpha (0-100 ng/ml) was added 0-4 8 h before total RNA was extracted. Northern blots were hybridized wit h P-32-TGF-beta 1, -beta 2, and -beta 3 cDNAs. In aged cells TNF-alpha increased their TGF-beta 1 (and -beta 2 and -beta 3) mRNA levels 5.4- fold (and > 10-fold), respectively, while in young cells all TGF-beta mRNAs remained almost undetectable during incubation with TNF-alpha. I n contrast, TNF-alpha and TSH had a highly significant stimulatory eff ect on the secretion rate of TGF-beta precursors in both young and old cells as measured in the mink lung cell bioassay. In summary, TNF-alp ha and TSH enhance TGF-beta transcription and/or mRNA stability in age d, but not young, FRTL-5 cells, while TNF-alpha and TSH increase trans lation and secretion of TGF-beta in young and aged cells.