LEUKEMIA INHIBITORY FACTOR MODULATES INTERLEUKIN-1-BETA-INDUCED ACTIVATION OF THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS

We have shown that leukemia inhibitory factor (LIF) is expressed in co rticotroph cells and stimulates POMC gene expression and ACTH secretio n in vivo and in vitro. We therefore examined the regulation of in vit ro and in vivo pituitary LIF expression by cytokines known to stimulat e the hypothalamo-pituitary-adrenal axis. In the corticotroph cell lin e AtT-20/D16v-F2, recombinant murine interleukin-lp (IL-1 beta; 0.1-10 .0 ng/ml) caused a 5- to 10-fold increase in LIF messenger RNA (mRNA) levels. LIF mRNA expression was induced as early as 1 h, peaked at 2 h , and still persistently elevated above the baseline after 8 h. This e ffect of IL-1 beta on LIF mRNA expression was abolished by preincubati on with human IL-1 receptor antagonist(100 ng/ml) or antimurine IL-1 b eta antibody (10 mu g/ml). Tumor necrosis factor-alpha (20 ng/ml) only modestly increased LIF mRNA, but was synergistic with IL-1 beta (up t o 2.5-fold). In contrast, IL-2 and IL-6 did not alter LIF mRNA. In C57 BL/6 mice, ip injection of 100 ng IL-1 beta increased plasma ACTH and corticosterone levels after 1 h (P < 0.02). In addition, pituitary LIF mRNA content was increased for up to 2 h in response to IL-1 beta. In comparison to wild-type (+/+) B6D2F1 mice, LIF knockout mice with a d eleted LIF gene (-/-) exhibited decreased plasma ACTH (631 +/- 61 vs. 376 +/- 50 pg/ml; P < 0.01) and corticosterone (783 +/- 85 vs. 433 +/- 51 ng/ml; P < 0.01) levels Ih after ip IL-1 beta administration. In c onclusion, corticotroph LIF mRNA expression is specifically stimulated by IL-1 beta and tumor necrosis factor-a. The attenuated hypothalamo- pituitary-adrenal response to IL-1 beta in LIF knockout mice indicates that the effect of IL-1 beta on ACTH secretion is modulated by LIF. T hus, LIF appears to function as an immune;neuroendocrine modulator sig naling the hypothalamopituitary-adrenal axis.