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

The pleiotropic cytokine leukemia inhibitory factor (LIF) is expressed in m urine 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: sc injection of complete Freund's a djuvant (CFA) and im administration of turpentine. Hypothalamic LIF gene ex pression was increased up to 5 days after CFA, and up to 24 h after turpent ine. LIF induction was concordant with elevated plasma ACTH and corticoster one levels and pituitary POMC messenger RNA (mRNA) expression. Pituitary le vels of LIF-inducible signaling inhibitor (SOCS 3) mRNA were stimulated S-f old after CFA and turpentine treatment. Tn contrast, in LIF knockout mice ( LIFKO) pituitary POMC mRNA levels and plasma ACTH and corticosterone respon ses to both inflammatory challenges were markedly lower than in wild-type ( WT) animals. Injection of exogenous LIF (5 mug) to turpentine-treeated LIFK O mice induces POMC gene expression. These results indicate that LIF is an essential component for the neuroendocrine response to inflammatory process es.