title: Endoplasmic Reticulum Stress and Chemokine Production in Cystic Fibrosis Airway Cells: Regulation by STAT3 Modulation.
abstract: Endoplasmic reticulum (ER) stress has been recognized to play an important role in chronic inflammatory diseases such as cystic fibrosis (CF), and targeting ER stress may be useful for alleviating damaging neutrophilic inflammation in CF airways. Cellular models were used in conjunction with data from a recent CF genome-wide association study (GWAS) meta-analysis to determine modulators of ER stress-mediated inflammation. Surprisingly, cells undergoing ER stress during inflammatory stimulation showed reduced interleukin 8 (IL-8) and CXCL1 secretion (P < .001). Neutralization of CXCL1 and IL-8 reduced neutrophil chemotaxis >50% to supernatants from IL-1β-stimulated CF airway epithelial cells (P < .01). The clinical importance of these chemokines was validated by association of CXCL1 and IL8 polymorphisms with changes in lung disease severity in patients with CF (n = 6365; IL8, P = .001; CXCL1, P = .001), confirming that targeting these chemokine pathways could help improve lung disease. We determined that production of these chemokines was partially controlled by ER stress in a signal transducer and activator of transcription 3 (STAT3)-dependent manner, whereby ER stress inhibited STAT3 activation. Our findings support a role for CXCL1 and IL-8 in CF lung disease severity and identify STAT3 as a modulating pathway. Targeting these pathways may help improve health outcomes in CF.
authors: Department of Microbiology & Immunology, University of British Columbia.
authors: Anthony C
authors: AC
authors: Tang
authors: Centre for Heart Lung Innovation, University of British Columbia and St Paul's Hospital.|Department of Pediatrics, Children's Hospital, University of British Columbia, Vancouver.
authors: Aabida
authors: A
authors: Saferali
authors: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Ontario, Canada.
authors: Gengming
authors: G
authors: He
authors: Centre for Heart Lung Innovation, University of British Columbia and St Paul's Hospital.
authors: Andrew J
authors: AJ
authors: Sandford
authors: Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Ontario, Canada.
authors: Lisa J
authors: LJ
authors: Strug
authors: Department of Microbiology & Immunology, University of British Columbia.|Department of Pediatrics, Children's Hospital, University of British Columbia, Vancouver.
authors: Stuart E
authors: SE
authors: Turvey
mesh_terms: D000328:Adult; D002460:Cell Line; D054360:Chemokine CXCL1; D003550:Cystic Fibrosis / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D016209:Interleukin-8; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: chemokines; endoplasmic reticulum stress; innate immunity