EFFECTS OF TUMOR-NECROSIS-FACTOR-ALPHA, INTERLEUKIN-1-BETA, AND INTERLEUKIN-6 ON TYPE-I IODOTHYRONINE 5'-DEIODINATION IN RAT-THYROID CELL-LINE, FRTL-5

Using a functioning rat thyroid cell line (FRTL-5), we studied the effects of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) on thyroidal type I iodothyronine 5'-deiodination (I-5'-deiodination) and on the expression of I-5'-deiodinase (I-5'-D) mRNA. After 24 h incubation in medium containing 0.5 mu M rT3 with a tracer amount of [I-125]rT3, radioactivity of released I-125(-) was counted, Deiodination in live FRTL-5 cells was enhanced about three times from the basal level by the addition of TSH and was inhibited markedly by propylthiouracil and dose dependently by T4. These results suggest the suitability of this model for investigating I-5'-deiodination in live thyroid tissue. Basal and TSH-induced I-5'-deiodination were significantly inhibited by 100 ng/liter of IL-1 beta and IL-6, and the inhibitory effect of TNF-alpha was seen over 1 mu g/liter. I-5'-deiodination was restored by removal of the cytokines, TSH-induced cAMP production and (Bu)(2)cAMP-induced I-5'-deiodination were also inhibited by the cytokines, Catalase, dexamethasone, and indomethacin did not abolish the inhibitory effects of the cytokines, Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a marked suppression of I-5'-D mRNA expression by IL-1 beta and IL-6, We conclude that these cytokines inhibit the thyroidal type I I-5'-deiodination in the order of potency IL-1 beta > IL-6 much greater than TNF-alpha, probably by decreasing the I-5'-D mRNA level, The site of inhibition by these cytokines may be distal to TSH-mediated cAMP production, and the inhibitory effects may also be exhibited by decreasing the TSH-induded generation of cAMP, The inhibitory effect of cytokines may not be associated with the phospholipase A(2) pathway or production of active oxygen species.