title: Intracellular insulin-like growth factor-1 induces Bcl-2 expression in airway epithelial cells.
abstract: Bcl-2, a prosurvival protein, regulates programmed cell death during development and repair processes, and it can be oncogenic when cell proliferation is deregulated. The present study investigated what factors modulate Bcl-2 expression in airway epithelial cells and identified the pathways involved. Microarray analysis of mRNA from airway epithelial cells captured by laser microdissection showed that increased expression of IL-1β and insulin-like growth factor-1 (IGF-1) coincided with induced Bcl-2 expression compared with controls. Treatment of cultured airway epithelial cells with IL-1β and IGF-1 induced Bcl-2 expression by increasing Bcl-2 mRNA stability with no discernible changes in promoter activity. Silencing the IGF-1 expression using short hairpin RNA showed that intracellular IGF-1 (IC-IGF-1) was increasing Bcl-2 expression. Blocking epidermal growth factor receptor or IGF-1R activation also suppressed IC-IGF-1 and abolished the Bcl-2 induction. Induced expression and colocalization of IC-IGF-1 and Bcl-2 were observed in airway epithelial cells of mice exposed to LPS or cigarette smoke and of patients with cystic fibrosis and chronic bronchitis but not in the respective controls. These studies demonstrate that IC-IGF-1 induces Bcl-2 expression in epithelial cells via IGF-1R and epidermal growth factor receptor pathways, and targeting IC-IGF-1 could be beneficial to treat chronic airway diseases.
authors.affiliation: Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
authors.forename: Hitendra S
authors.initials: HS
authors.lastname: Chand
authors.forename: Jennifer Foster
authors.initials: JF
authors.lastname: Harris
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Mebratu
authors.forename: Yangde
authors.initials: Y
authors.lastname: Chen
authors.forename: Paul S
authors.initials: PS
authors.lastname: Wright
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003550:Cystic Fibrosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D020868:Gene Silencing; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000276:immunology*; D051381:Rats; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D014028:Tobacco Smoke Pollution; C519530:insulin-like growth factor-1, mouse; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; C541485:EGFR protein, mouse; C483803:Egfr protein, rat; D066246:ErbB Receptors