HUMAN AND MURINE PITUITARY EXPRESSION OF LEUKEMIA INHIBITORY FACTOR -NOVEL INTRAPITUITARY REGULATION OF ADRENOCORTICOTROPIN HORMONE SYNTHESIS AND SECRETION

Leukemia inhibitory factor (LIF) gene expression was detected in human fetal pituitary tissue by expression of LIF mRNA transcripts, protein immunocytochemistry, and immunoelectron microscopy, Fetal LIF immunor eactivity colocalized with 30% of ACTH-expressing cells, similar to 20 % of somatotrophs, and similar to 15% of non-hormone-expressing cells. LIF was also strongly expressed in normal adult pituitary and in four growth hormone-producing and two ACTH-producing adenomas, but not in eight nonfunctioning pituitary tumors. Culture of fetal cells expressi ng surface LIF-binding sites demonstrated predominance of in vitro ACT H secretion as compared with other pituitary hormones. In AtT-20 murin e cells, LIF (ED(50) 10 pM) stimulated basal proopiomelanocortin mRNA levels by 40%, and corticotropin-releasing hormone-induced ACTH secret ion (two- to threefold), as did oncostatin M (ED(50) 30 pM), a related peptide. ACTH responses were not further enhanced by both cytokines t ogether, which is consistent with their shared receptor. Anti-LIF anti serum neutralized basal and LIF-induced ACTH secretion, suggesting aut ocrine regulation of ACTH by LIF. The results show that human pituitar y cells express the LIF gene and LIF-binding sites, predominantly in c orticotrophs, Pituitary LIF expression and LIF regulation of proopiome lanocortin and ACTH reflect an intrapituitary role for LIF in modulati ng early embryonic determination of specific human pituitary cells and as a paracrine or autocrine regulator of mature ACTH.