We have shown that leukemia inhibitory factor (LIF) is expressed in corticotroph cells and stimulates POMC gene expression and ACTH secretion in vivo and in vitro. We therefore examined the regulation of in vitro and in vivo pituitary LIF expression by cytokines known to stimulate the hypothalamo-pituitary-adrenal axis. In the corticotroph cell line AtT-20/D16v-F2, recombinant murine interleukin-1β (IL-1β; 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 effect of IL-1β on LIF mRNA expression was abolished by preincubation with human IL-1 receptor antagonist (100 ng/ml) or antimurine IL-1β antibody (10 μg/ml). Tumor necrosis factor-α (20 ng/ml) only modestly increased LIF mRNA, but was synergistic with IL-1β (up to 2.5-fold). In contrast, IL-2 and IL-6 did not alter LIF mRNA. In C57BL/6 mice, ip injection of 100 ng IL-1β 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-1β. In comparison to wild-type (+/+) B6D2F1 mice, LIF knockout mice with a deleted 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 1 h after ip IL-1β administration. In conclusion, corticotroph LIF mRNA expression is specifically stimulated by IL-1β and tumor necrosis factor-α. The attenuated hypothalamo-pituitary-adrenal response to IL-1β in LIF knockout mice indicates that the effect of IL-1β on ACTH secretion is modulated by LIF. Thus, LIF appears to function as an immune-neuroendocrine modulator signaling the hypothalamo-pituitary-adrenal axis.