We have recently shown expression of leukemia inhibitory factor (LIF) in human fetal pituitary tissue and its in vitro induction of POMC transcription. We now use qualitative and semiquantitative RT-PCR to demonstrate that LIF and LIF-receptor (LIF-R) are constitutively expressed in the normal mouse hypothalamus and pituitary. Hypothalamic and pituitary LIF and LIF-R are significantly induced (up to 6- and 4-fold, respectively) in vivo in response to lipopolysaccharide endotoxin (LPS) administered to B6D2F1 and C57BL/6 mice. In contrast to the nearly exclusive expression of matrix-associated LIF messenger RNA (mRNA) in control hypothalamus and pituitary, both diffusible and matrix-associated LIF mRNA alternate transcripts are induced by LPS. Furthermore, the time course of peripheral ACTH-response to LPS peaks at 60 min, whereas hypothalamic LIF mRNA increase occurs at 30 min and pituitary LIF induction occurs at 60 min. These results show that mLIF is a novel LPS-inducible proinflammatory neuroendocrine cytokine and the alternatively spliced diffusible LIF may play a paracrine role in activating pituitary ACTH secretion in synergy with hypothalamic CRH, implying a mechanism for central nervous system cytokine responses to immune signals.