Leukemia inhibitory factor mediates the hypothalamic pituitary adrenal axis response to inflammation

The pleiotropic cytokine leukemia inhibitory factor (LIF) is expressed in murine hypothalamus and pituitary and increases POMC gene transcription and ACTH secretion in vitro and in vivo. As hypothalamic pituitary adrenal (HPA) axis activation during inflammation is an important protective mechanism, we determined whether LIF stimulates the HPA inflammatory stress response. Two experimental models were employed: s.c. injection of complete Freund's adjuvant (CFA) and i.m. administration of turpentine. Hypothalamic LIF gene expression was increased up to 5 days after CFA, and up to 24 h after turpentine. LIF induction was concordant with elevated plasma ACTH and corticosterone levels and pituitary POMC messenger RNA (mRNA) expression. Pituitary levels of LIF-inducible signaling inhibitor (SOCS 3) mRNA were stimulated 3-fold after CFA and turpentine treatment. In contrast, in LIF knockout mice (LIFKO) pituitary POMC mRNA levels and plasma ACTH and corticosterone responses to both inflammatory challenges were markedly lower than in wild-type (WT) animals. Injection of exogenous LIF (5 microg) to turpentine-treated LIFKO mice induces POMC gene expression. These results indicate that LIF is an essential component for the neuroendocrine response to inflammatory processes.