title: Direct regulation of IGF-binding protein 1 promoter by interleukin-1β via an insulin- and FoxO-1-independent mechanism.
abstract: The level of insulin-like growth factor-binding protein 1 (IGFBP1), a liver-produced serum protein that regulates insulin-like growth factor-I bioactivity, glucose homeostasis, and tissue regeneration, increases during inflammation. This manuscript describes a novel pathway for the regulation of hepatic IGFBP1 mRNA and protein levels by interleukin (IL)-1β. Experiments with the luciferase reporter system show that IL-1β stimulates transcriptional activity from the 1-kb promoter region of IGFBP1. Although IL-1β stimulation suppresses the insulin activation of protein kinase B, the major upstream regulator of IGFBP1 mRNA transcription, the induction of IGFBP1 by IL-1β did not require an intact insulin response element. Furthermore, neither overexpression nor silencing of FoxO-1 had any effect on the IL-1β-induced increase in IGFBP1 mRNA levels and promoter activity. However, inhibition of the ERK MAP kinases effectively prevented the IL-1β effects. Inhibition of neutral sphingomyelinase, a key player in the IL-1β signaling cascade that acts upstream of ERK, also suppressed the IL-1β effects, while increasing the ceramide, through the addition of C2-ceramide or via treatment with exogenous sphingomyelinase, was sufficient to induce IGFBP1 promoter-driven luciferase activity. Studies in primary rat hepatocytes where the levels of neutral sphingomyelinase were either elevated or suppressed using adenoviral constructs affirmed the key role of neutral sphingomyelinase and ceramide (exerted likely through ERK activation) in the IL-1β-induced IGFBP1 production. Finally, the IL-1β effects on IGFBP1 mRNA production and protein secretion could be abolished by the addition of insulin, either at very late time points or at very high doses.
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: D
authors.initials: D
authors.lastname: Banerjee
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: A
authors.initials: A
authors.lastname: Dobierzewska
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: S
authors.initials: S
authors.lastname: Sathishkumar
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: A A
authors.initials: AA
authors.lastname: Karakashian
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: N V
authors.initials: NV
authors.lastname: Giltiay
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky mnikolo@uky.edu.
authors.forename: M N
authors.initials: MN
authors.lastname: Nikolova-Karakashian
mesh_terms: D000818:Animals; D015153:Blotting, Western; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D053583:Interleukin-1beta; C064769:N-acetylsphingosine; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D013108:Sphingomyelin Phosphodiesterase; D005947:Glucose; D013110:Sphingosine
keywords: ceramide; inflammation; insulin-like growth factor-binding protein-1; interleukin-1β; sphingomyelinase