title: Endoplasmic Reticulum Stress Is a Danger Signal Promoting Innate Inflammatory Responses in Bronchial Epithelial Cells.
abstract: Endoplasmic reticulum (ER) stress is associated with chronic pulmonary inflammatory diseases. We hypothesized that the combined activation of both Toll-like receptor (TLR) signaling and ER stress might increase inflammatory reactions in otherwise tolerant airway epithelial cells. Indeed, ER stress resulted in an increased response of BEAS-2B and human primary bronchial epithelial cells to pathogen-associated molecular pattern stimulation with respect to IL6 and IL8 production. ER stress elevated p38 and ERK MAP kinase activation, and pharmacological inhibition of these kinases could inhibit the boosting effect. Knockdown of unfolded protein response signaling indicated that mainly PERK and ATF6 were responsible for the synergistic activity. Specifically, PERK and ATF6 mediated increased MAPK activation, which is needed for effective cytokine secretion. We conclude that within airway epithelial cells the combined activation of TLR signaling and ER stress-mediated MAPK activation results in synergistic proinflammatory activity. We speculate that ER stress, present in various chronic pulmonary diseases, boosts TLR signaling and therefore proinflammatory cytokine production, thus acting as a costimulatory danger signal.
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Mijošek
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.forename: Heike
authors.initials: H
authors.lastname: Zabeck
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Dalpke
authors.forename: Michael
authors.initials: M
authors.lastname: Weitnauer
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D001980:Bronchi / Q000473:pathology*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000276:immunology*; D059865:Endoplasmic Reticulum Stress / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000276:immunology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D048049:Extracellular Signal-Regulated MAP Kinases; D015850:Interleukin-6; D016209:Interleukin-8; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C497111:ATF6 protein, human