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Influence of Cytokines on Growth and Differentiated Function of FRTL5 Cells^*

M. ZAKARIJA and J. M. McKENZIE

Department of Medicine, University of Miami School of Medicine Miami, Florida 33101

Address requests for reprints to: Margita Zakarija, MD, Department of Medicine (R-93), University of Miami School of Medicine, P.O. Box 016760, Miami, Florida 33101.

Abstract

A functioning rat thyroid cell line (FRTL5) was used to study interactions of TSH with interferon- (IFN) and tumor necrosis factor- (TNF). We examined effects on growth and differentiated function. Growth was assessed by DNA, incorporation of [³H]thymidine ([³H]Tdr) into DNA, and cell number; uptake of ¹²⁵I (I^– uptake) and the concentration of cAMP were measured simultaneously with growth assessment. IFN stimulated the 30-min I^– uptake and enhanced the effect of TSH. TNF had minimal effects on growth indices (slight increase in [³H]Tdr incorporation) and had no influence on I^– uptake; it inhibited TSH stimulation of both growth and I^– uptake. When combined, IFN and TNFa synergized in inhibiting TSH-stimulated growth. By itself TNFa inhibited stimulation of I^– uptake by TSH, but augmented the enhancement seen with IFN. The influence of calf serum (CS) was to increase the rate of incorporation of [³H]Tdr, but a similar qualitative pattern for the actions of the cytokines remained. A reverse profile (stimulation by IFN, inhibition by TNF, and stimulation by the combination) was seen for I^– uptake, with CS increasingly diminishing all values. TSH stimulation of growth was progressively effective with increments of CS in the medium, but consistently there was inhibition that was greater with IFN than with TNF and was almost total with the combined cytokines. Stimulation of I^– uptake by TSH was enhanced by IFN, reduced by TNF, and, when serum was present, increased to a degree that was greater than additive by the combined cytokines. Growth stimulation by insulin or insulin-like growth factor-I was inhibited partially by the individual cytokines and completely by the combination. Both insulin and insulin-like growth factor-I inhibited TSH stimulation of I^– uptake, but similar stimulation by the cytokines was not affected. Simultaneous with inhibition of TSH-stimulated growth, both IFN and TNF enhanced cAMP accumulation. The mechanism of these multiple effects of IFN and TNF, especially on the actions of TSH, may not currently be fully explained, but they almost certainly reflect differing modes of action. The relevance to thyroid function in man is conjectural. Especially in Graves' disease, where thyroid infiltration with cells that secrete these cytokines is common, it seems probable that both IFN and TNF will have significant influences on both growth and differentiated cell function.

Footnotes

^* This work was supported by NIH Grant DK-31391.

Kathleen and Stanley Glaser Professor of Medicine.

Received March 31, 1989.

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