In vivo and in vitro regulation of thyroid leukemia inhibitory factor (LIF): Marker of hypothyroidism

Several cytokines regulate thyroid function and may be involved in the path ogenesis of thyroid disorders, including euthyroid sick syndrome. Leukemia inhibitory factor (LIF), a neuroimmune pleiotropic cytokine, was measured t o assess its role in hypothalamic-pituitary-thyroid function. Mean circulat ing serum LIF levels in 10 hypothyroid patients [TSH, 23 +/- 0.5 mIU/L (mea n +/- SEM); free T-4, 0.77 +/- 0.1 ng/dL] was 0.29 +/- 0.04 ng/mL, 145% hig her (P < 0.04) than in 20 normal subjects (LIF, 0.20 +/- 0.02 ng/mL; TSH, 2 .23 +/- 0.21 mIU/L; free T-4, 1.23 +/- 0.04 ng/dL) but was not different fr om those in 10 hyperthyroid patients (LIF, 0.21 +/- 0.03 ng/mL; TSH, 0.01 /- 0.00 mIU/L; free T-4, 3.63 +/- 0.51 ng/dL). Serum LIF concentrations lin early correlated with serum TSH in the 40 samples (r = 0.58, P < 0.001). Wh en T-4 (1-8 mu g/kg.day) was administered to cynomolgus monkeys with methim azole-induced hypothyroidism, serum T-4 and T-3 levels increased appropriat ely, and TSH and LIF concentrations decreased. When methimazole was given a lone, both serum TSH (146 +/- 30 mIU/L) and LIF (8.84 +/- 0.49 ng/mL) were markedly induced. When methimazole together with T-4 (>2 mu g/kg.day) was a dministered, both serum TSH (7.5 +/- 1.2 mIU/L) and LIF (6.22 +/- 0.31 ng/m L) were lowered (P < 0.01). Monkey serum LIF levels and log TSH levels also correlated (r = 0.72, P < 0.01). Cultured thyroid carcimona cells produced LIF (9.2 ng/10(6) cells/48 h). TSH (100 mIU/mL) and interleukin (IL)-6 (10 nmol/L) stimulated in vitro LIF secretion from the cells by 170 +/- 12% (P < 0.05) and 261 +/- 8% (P < 0.05), respectively. Dexamethasone (1 mu mol/L ) inhibited basal LIF concentration by 83% (P < 0.05), whereas TSH and IL-6 stimulated LIF by 52% (P = 0.04) and 42% (P = 0.03), respectively. However , using Northern blot analysis, we could not observe induction of LIF mRNA by TSH, suggesting that LIF regulation by TSH may be due to stimulation of secretion. The results show that the thyroid gland is a source of LIF produ ction; TSH, IL-6, and glucocorticoid influence thyroid cell LIF expression. The correlation between TSH and LIF suggests that LIF may participate in t he physiologic regulation of hypothalamic-pituitary-thyroid function.