Leukemia inhibitory factor regulates prolactin secretion in prolactinoma and lactotroph cells.
Leukemia inhibitory factor (LIF) stimulates the hypothalamic-pituitary-adrenal axis, and transgenic mice overexpressing pituitary LIF develop Cushing-like syndrome accompanied by reduced prolactin (PRL) expression. Effects of LIF were, therefore, tested on PRL expression in human prolactinomas and normal and tumorous rat lactotrophs. Normal human pituitary tissue expressed LIF, as well as the LIF receptor (LIFR) signaling subunits, gp130 and LIFR. Although all of 19 prolactinomas tested expressed gp130 and LIFR subunit mRNA and immunoreactive protein, only 3 of 19 prolactinomas expressed LIF mRNA. All of four prolactinomas had no detectable LIF immunoreactivity, in contrast to all other pituitary tumor types that expressed LIF. LIF (5 nM) treatment reduced PRL secretion in primary human prolactinoma cultures by up to 42% (P < 0.0005), an effect that was surprisingly blocked by sulpiride, a D2-like dopamine receptor antagonist. LIF (5 nM) also suppressed PRL levels in primary rat pituitary cultures by 70% (P < 0.005), and in rat MMQ pituitary tumor cells, and this effect was also reversed by sulpiride (200 micro M). D2R agonist suppression of PRL was not additive with LIF. GH levels in these cells were unchanged by LIF, consistent with a selective effect on PRL. Transfection of human long-form D2R into an LIF-resistant MMQ cell clone restored LIF responsiveness. These results show that even though human prolactinomas express gp130 and LIFR, and respond to exogenous LIF, albeit less than normal lactotrophs, they are largely devoid of LIF. These observations indicate a role for LIF in loss of autocrine PRL suppression contributing to unrestrained prolactinomas PRL secretion. Moreover, PRL suppression by LIF may be mediated by gp130 and D2R interaction.
Ben-Shlomo
Anat
A
Division of Endocrinology and Metabolism, Cedars-Sinai Research Institute, University of California School of Medicine, Los Angeles, California 90048, USA.
Miklovsky
Irina
I
Ren
Song-Guang
SG
Yong
William H
WH
Heaney
Anthony P
AP
Culler
Michael D
MD
Melmed
Shlomo
S
D000236:Adenoma; D000818:Animals; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015870:Gene Expression; D006131:Growth Inhibitors / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000235:genetics*; D010903:Pituitary Gland, Anterior / Q000166:cytology* / Q000378:metabolism; D010911:Pituitary Neoplasms; D011388:Prolactin / Q000378:metabolism*; D015175:Prolactinoma; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics; D013469:Sulpiride / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D017448:Receptors, Dopamine D2; D013469:Sulpiride; D011388:Prolactin