Leukemia inhibitory factor (LIF) stimulates proopiomelanocortin (POMC) expression in a corticotroph cell line. Role of STAT pathway.
We recently described the expression of leukemia inhibitory factor (LIF) in human fetal and murine corticotrophs. LIF and the related cytokine oncostatin M induced basal, and corticotropin-releasing hormone (CRH) induced proopiomelanocortin (POMC) mRNA and ACTH secretion in AtT20 cells. LIF signaling and regulation of POMC gene transcription were therefore tested. Dexamethasone inhibited both basal- and LIF-induced ACTH secretion (P<0.05) and LIF induction of ACTH was also attenuated by immuneutralization of either the LIF receptor (35%, P<0.05) or the gp130 affinity converter (41%, P<0.05). These antisera also attenuated basal ACTH secretion in the absence of added ligand (P<0.05). To examine intrapituitary LIF signaling, phosphorylation of post-receptor substrates was measured. 1 nM LIF rapidly induced tyrosyl phosphorylation of STAT 1 and STAT 3 proteins, as well as tyrosyl phosphorylation of a 115-kD protein, coimmunoprecipitated with STAT 1. The transfected rat POMC promoter -706/+64, fused to the luciferase reporter gene, was induced by LIF, which exerted strong (18-fold) synergy with CRH. Deletion of the major CRH responsive region in POMC (-323/-166) abolished CRH induction of transcription and severely limited LIF synergy. Although 8 bromo cAMP or forskolin modestly enhanced POMC transcription (2.8-fold), LIF markedly potentiated (7.4-fold) these cAMP activators. These results demonstrate that corticotroph LIF action is receptor mediated and involves activation of STAT signaling pathways. LIF potently synergizes with both CRH and cAMP induction of POMC transcription. This novel intrapituitary signaling mechanism may mediate a neuroimmune pituitary interface.
Ray
D W
DW
Department of Medicine, Cedars-Sinai Research Institute-UCLA School of Medicine, Los Angeles, California 90048, USA.
Ren
S G
SG
Melmed
S
S
D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005333:Fetus; D015870:Gene Expression / Q000187:drug effects*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008156:Luciferases / Q000096:biosynthesis; D008222:Lymphokines / Q000494:pharmacology*; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D010902:Pituitary Gland / Q000378:metabolism; D010911:Pituitary Neoplasms; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D018121:Receptors, Cytokine / Q000276:immunology / Q000502:physiology; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507842:Lifr protein, rat; D008222:Lymphokines; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins; D053683:Oncostatin M; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D008156:Luciferases