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In Vivo and in Vitro Regulation of Thyroid Leukemia Inhibitory Factor (LIF): Marker of Hypothyroidism¹

Department of Medicine (S.G.R., J.S., X.L., G.D.B., S.M.), Cedars-Sinai Research Institute; Endocrine Research Laboratory West Los Angeles (J.M.H.), VA Medical Center; UCLA School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Division of Endocrinology & Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Blvd; Room B-131, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu

Several cytokines regulate thyroid function and may be involved in the pathogenesis of thyroid disorders, including euthyroid sick syndrome. Leukemia inhibitory factor (LIF), a neuroimmune pleiotropic cytokine, was measured to assess its role in hypothalamic-pituitary-thyroid function. Mean circulating serum LIF levels in 10 hypothyroid patients [TSH, 23 ± 0.5 mIU/L (mean ± SEM); free T₄, 0.77 ± 0.1 ng/dL] was 0.29 ± 0.04 ng/mL, 145% higher (P < 0.04) than in 20 normal subjects (LIF, 0.20 ± 0.02 ng/mL; TSH, 2.23 ± 0.21 mIU/L; free T₄, 1.23 ± 0.04 ng/dL) but was not different from those in 10 hyperthyroid patients (LIF, 0.21 ± 0.03 ng/mL; TSH, 0.01 ± 0.00 mIU/L; free T₄, 3.63 ± 0.51 ng/dL). Serum LIF concentrations linearly correlated with serum TSH in the 40 samples (r = 0.58, P < 0.001). When T₄ (1–8 µg/kg·day) was administered to cynomolgus monkeys with methimazole-induced hypothyroidism, serum T₄ and T₃ levels increased appropriately, and TSH and LIF concentrations decreased. When methimazole was given alone, both serum TSH (146 ± 30 mIU/L) and LIF (8.84 ± 0.49 ng/mL) were markedly induced. When methimazole together with T₄ (>2 µg/kg·day) was administered, both serum TSH (7.5 ± 1.2 mIU/L) and LIF (6.22 ± 0.31 ng/mL) 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/10⁶ 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 µmol/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 production; TSH, IL-6, and glucocorticoid influence thyroid cell LIF expression. The correlation between TSH and LIF suggests that LIF may participate in the physiologic regulation of hypothalamic-pituitary-thyroid function.