title: Atypical activation of the unfolded protein response in cystic fibrosis airway cells contributes to p38 MAPK-mediated innate immune responses.
abstract: Inflammatory lung disease is the major cause of morbidity and mortality in cystic fibrosis (CF); understanding what produces dysregulated innate immune responses in CF cells will be pivotal in guiding the development of novel anti-inflammatory therapies. To elucidate the molecular mechanisms that mediate exaggerated inflammation in CF following TLR signaling, we profiled global gene expression in immortalized human CF and non-CF airway cells at baseline and after microbial stimulation. Using complementary analysis methods, we observed a signature of increased stress levels in CF cells, specifically characterized by endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and MAPK signaling. Analysis of ER stress responses revealed an atypical induction of the UPR, characterized by the lack of induction of the PERK-eIF2α pathway in three complementary model systems: immortalized CF airway cells, fresh CF blood cells, and CF lung tissue. This atypical pattern of UPR activation was associated with the hyperinflammatory phenotype in CF cells, as deliberate induction of the PERK-eIF2α pathway with salubrinal attenuated the inflammatory response to both flagellin and Pseudomonas aeruginosa. IL-6 production triggered by ER stress and microbial stimulation were both dependent on p38 MAPK activity, suggesting a molecular link between both signaling events. These data indicate that atypical UPR activation fails to resolve the ER stress in CF and sensitizes the innate immune system to respond more vigorously to microbial challenge. Strategies to restore ER homeostasis and normalize the UPR activation profile may represent a novel therapeutic approach to minimize lung-damaging inflammation in CF.
authors.affiliation: Department of Paediatrics, BC Children's Hospital and Child & Family Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Blohmke
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Mayer
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Tang
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Hirschfeld
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fjell
authors.forename: Marc A
authors.initials: MA
authors.lastname: Sze
authors.forename: Reza
authors.initials: R
authors.lastname: Falsafi
authors.forename: Shirley
authors.initials: S
authors.lastname: Wang
authors.forename: Karolynn
authors.initials: K
authors.lastname: Hsu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Chilvers
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
mesh_terms: D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000150:complications / Q000276:immunology* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000276:immunology; D005408:Flagellin / Q000276:immunology / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D011014:Pneumonia / Q000150:complications / Q000276:immunology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000276:immunology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D005408:Flagellin; D015850:Interleukin-6; D013890:Thiourea; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C496827:salubrinal