Cytokine-dependent gp130 receptor subunit regulates human fetal pituitary adrenocorticotropin hormone and growth hormone secretion.
We have shown recently that leukemia inhibitory factor (LIF) and oncostatin M (OSM), two members of the gp130-dependent cytokine family, stimulate murine proopiomelanocortin (POMC) transcription and adrenocorticotropin hormone (ACTH) secretion. LIF and corticotropin-releasing hormone (CRH) also synergistically induced in vivo ACTH secretion in fetal nonhuman primates. To elucidate the role of the gp130-related cytokines in human pituitary hormone regulation, we tested expression of gp130-related cytokine receptors in human fetal pituitaries. Using RT-PCR, mRNA expression of receptors for LIF, IL-6, and CRH, and the gp130 subunit, were all detected in fetal pituitaries of 18- and 31-wk gestation. Recombinant human IL-6, LIF, and OSM treatments of primary human fetal pituitary cultures (16-31 wk) increased ACTH secretion by up to 48% (P < 0.05) using doses of 1 nM, and when fetal cultures were cotreated with CRH, ACTH was induced five- to sixfold as compared to CRH alone (three- to fourfold; P = 0.01). Incubation with gp130-specific antibody suppressed basal and cytokine-stimulated ACTH secretion (alone or with CRH) from human fetal cells. Human POMC promoter -879/+6 fused to the luciferase reporter gene and transfected into AtT-20 cells, was stimulated by LIF (7-fold), which also exerted strong (22-fold) synergy with CRH on POMC transcription. Growth hormone (GH) release from fetal cultures was modestly stimulated (15-31%, P < 0.05), while other anterior pituitary hormones were not altered by these cytokines. Thus, physiologic concentrations of the gp130-related cytokines have direct effects on ACTH and GH regulation in the human pituitary, indicating that gp130-dependent signals serve as a paracrine system controlling early human pituitary function.
Shimon
I
I
Department of Medicine, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA.
Yan
X
X
Ray
D W
DW
Melmed
S
S
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000494:pharmacology*; D018076:DNA, Complementary; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006131:Growth Inhibitors / Q000494:pharmacology; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection / Q000235:genetics
D000906:Antibodies; D015703:Antigens, CD; D016207:Cytokines; D018076:DNA, Complementary; D006131:Growth Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008562:Membrane Glycoproteins; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D053683:Oncostatin M; D019382:Human Growth Hormone; D050822:Cytokine Receptor gp130; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone