Regulation of prohormone convertase 1 (PC1) by gp130-related cytokines.
The processing of pro-opiomelanocortin (POMC) to generate bioactive ACTH in the anterior pituitary is mediated by prohormone convertase 1 (PC1). Leukemia inhibitory factor (LIF) and interleukin 6 (IL-6), two cytokines sharing the common gp130 receptor subunit and functioning through activation of the intracellular JAK/STAT pathway, induce POMC synthesis and ACTH release. We investigated the effects of LIF and IL-6 on PC1 expression and its subsequent processing of POMC. A significant time-dependent up-regulation of both PC1 protein and mRNA by LIF and IL-6 was seen in mouse corticotroph AtT-20 cells. IL-6 or LIF increased the synthesis of ACTH-related products with a concomitant increase in bioactive 5 and 13 kDa ACTH indicating coordinated regulation of substrate and processing enzyme. AtT-20 cells transiently transfected with a human PC1-promoter-luciferase reporter construct and treated with LIF or IL-6 showed significantly increased luciferase activity. Additionally, lipopolysaccharide (LPS) administration to rats resulted in an increase in both pituitary PC1 and POMC mRNA. These findings suggest that the ACTH increase induced by LIF and IL-6 is due to both increased POMC synthesis as well as increased POMC processing by up-regulation of PC1. These two coordinately regulated processing events probably exert central roles in the pathophysiological response to some stresses, such as inflammatory stress.
Li
Q L
QL
Department of Medicine, Cedars-Sinai Research Institute-UCLA School of Medicine, Los Angeles, CA 90048, USA.
Jansen
E
E
Friedman
T C
TC
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D002457:Cell Extracts; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008070:Lipopolysaccharides / Q000494:pharmacology; D008222:Lymphokines / Q000378:metabolism / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D010902:Pituitary Gland / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D045664:Proprotein Convertase 1; D043484:Proprotein Convertases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018121:Receptors, Cytokine / Q000378:metabolism / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D053606:Receptors, OSM-LIF; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D015703:Antigens, CD; D002457:Cell Extracts; D006131:Growth Inhibitors; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; C494201:Il6st protein, rat; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; C507842:Lifr protein, rat; D008070:Lipopolysaccharides; D008222:Lymphokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; D053606:Receptors, OSM-LIF; D050822:Cytokine Receptor gp130; D011333:Pro-Opiomelanocortin; D043484:Proprotein Convertases; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1; D016282:Aspartic Acid Endopeptidases