Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the gp130 family. LIF is induced peripherally and within the brain during inflammatory or chronic autoimmune diseases and is a potent stimulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here we investigated the role of LIF in mediating glucocorticoid receptor (GR) expression in the HPA axis. LIF treatment (3 µg/mouse, i.p.) markedly decreased GR mRNA levels in murine hypothalamus (5-fold, p<0.01) and pituitary (1.7-fold, p<0.01) and down-regulated GR protein levels. LIF decreased GR expression in murine corticotroph cell line AtT20 within 2 hours, and this effect was sustained for 8 hours after treatment. LIF-induced GR mRNA reduction was abrogated in AtT20 cells overexpressing dominant-negative mutants of STAT3, indicating that intact Jak-STAT signaling is required to mediate LIF effects on GR expression. Conversely, mice with LIF deficiency exhibited increased GR mRNA levels in the hypothalamus and pituitary (3.5-fold, and 3.5-fold, respectively; p<0.01 for both) and increased GR protein expression when compared with wild type littermates. The suppressive effects of dexamethasone on GR were more pronounced in LIF-null animals. These data suggest that LIF maintains the HPA axis activation by decreasing GR expression, and raise the possibility that LIF may contribute to the development of central glucocorticoid resistance during inflammation.