Leukemia Inhibitory Factor Regulates Proopiomelanocortin Transcriptiona

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    Supported by NIH Grant DK 42792 and by the Endocrine Fellows Foundation (D.R.). This work was presented at the 1996 AAP meeting in Washington, DC and formed the basis of a complete manuscript published in J. Clin. Invest. (1996) 97: 1852-1859.

Address for correspondence: Shlomo Melmed, M.D., Division of Endocrinology & Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Blvd., B-131, Los Angeles, CA 90048. Telephone: 310-855-4691; Fax: 310-967-0119–.

Abstract

Abstract: Leukemia inhibitory factor (LIF), a pleiotropic cytokine, is expressed in both fetal and adult pituitary tissue, and LIF immunoreactivity is found in functional human pituitary tumors. LIF induces basal, and augments CRH-induced, POMC mRNA and ACTH secretion from AtT20 cells. Therefore, we examined LIF signaling and LIF regulation of POMC expression in AtT20 cells. Immunoneutralization studies demonstrated the dependence of LIF action on both the specific LIF receptor (35% inhibition; p < 0.05) and also the gpl30 affinity converter (41% inhibition; p < 0.05). These antisera also attenuate basal ACTH secretion without added LIF. LIF rapidly induced tyrosyl phosphorylation of both STAT lα, and STATβ and also induced phosphorylation of a novel STAT lα related protein p115. LIF induced POMC transcription (−706/+64) and strikingly potentiated CRH action (up to 18-fold induction). This synergy involved cAMP-dependent pathways, as forskolin action was also potentiated by LIF. Deletion of the major CRH-responsive region in POMC (-323/-166) abolished both CRH and LIF action on POMC transcription. Thus LIF action in pituitary corticotrophs is dependent on LIF receptor heterodimerisation with gpl30 and involves STAT protein tyrosyl phosphorylation. LIF enhances POMC transcription and strongly potentiates the well-documented action of CRH on the POMC gene. These results define a subcellular mechanism for an immuno-neuroendocrine interface between peripheral afferent signals and the HPA axis.

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