title: Elevated miR-155 promotes inflammation in cystic fibrosis by driving hyperexpression of interleukin-8.
abstract: Cystic Fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung arising from profound expression of inflammatory genes, including interleukin-8 (IL-8). We have previously reported that IL-8 mRNA is stabilized in CF lung epithelial cells, resulting in concomitant hyperexpression of IL-8 protein. However, the mechanistic link between mutations in CFTR and acquisition of the proinflammatory phenotype in the CF airway has remained elusive. We hypothesized that specific microRNAs (miRNAs) might mediate this linkage. To identify the potential link, we screened an miRNA library for differential expression in ΔF508-CFTR and wild type CFTR lung epithelial cell lines. Of 22 differentially and significantly expressed miRNAs, we found that expression of miR-155 was more than 5-fold elevated in CF IB3-1 lung epithelial cells in culture, compared with control IB3-1/S9 cells. Clinically, miR-155 was also highly expressed in CF lung epithelial cells and circulating CF neutrophils biopsied from CF patients. We report here that high levels of miR-155 specifically reduced levels of SHIP1, thereby promoting PI3K/Akt activation. However, overexpressing SHIP1 or inhibition of PI3K in CF cells suppressed IL-8 expression. Finally, we found that phospho-Akt levels were elevated in CF lung epithelial cells and were specifically lowered by either antagomir-155 or elevated expression of SHIP1. We therefore suggest that elevated miR-155 contributes to the proinflammatory expression of IL-8 in CF lung epithelial cells by lowering SHIP1 expression and thereby activating the PI3K/Akt signaling pathway. These data suggest that miR-155 may play an important role in the activation of IL-8-dependent inflammation in CF.
authors.affiliation: Department of Health Systems, Risk, and Contingency Management, Graduate School of Nursing, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Nagaraja S
authors.initials: NS
authors.lastname: Balakathiresan
authors.forename: Clifton
authors.initials: C
authors.lastname: Dalgard
authors.forename: Usha
authors.initials: U
authors.lastname: Gutti
authors.forename: David
authors.initials: D
authors.lastname: Armistead
authors.forename: Cathy
authors.initials: C
authors.lastname: Jozwik
authors.forename: Meera
authors.initials: M
authors.lastname: Srivastava
authors.forename: Harvey B
authors.initials: HB
authors.lastname: Pollard
authors.forename: Roopa
authors.initials: R
authors.lastname: Biswas
mesh_terms: D002460:Cell Line; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D000072181:Inositol Polyphosphate 5-Phosphatases; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
chemical_list: C505032:CFTR protein, human; C508606:CXCL8 protein, human; D016209:Interleukin-8; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases