title: RelB attenuates cigarette smoke extract-induced apoptosis in association with transcriptional regulation of the aryl hydrocarbon receptor.
abstract: Chronic obstructive pulmonary disease (COPD) is a chronic and prevalent respiratory disease caused primarily by long term inhalation of cigarette smoke. A major hallmark of COPD is elevated apoptosis of structural lung cells including fibroblasts. The NF-κB member RelB may suppress apoptosis in response to cigarette smoke, but its role in lung cell survival is not known. RelB may act as a pro-survival factor by controlling the expression of superoxide dismutase 2 (SOD2). SOD2 is also regulated by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that suppresses cigarette smoke-induced apoptosis. As the AhR is also a binding partner for RelB, we speculate that RelB suppresses cigarette smoke-induced apoptosis by regulating the AhR. Using an in vitro model of cigarette smoke exposure (cigarette smoke extract [CSE]), we found that CSE down-regulated RelB expression in mouse lung fibroblasts, which was associated with elevated levels of cleaved PARP. Genetic ablation of RelB elevated CSE-induced apoptosis, including chromatin condensation, and reduced mitochondrial function. There was also more reactive oxygen species production in RelB-/-cells exposed to CSE. While there was no alteration in Nrf2 expression or localization between RelB-/-and wild type cells in response to CSE, RelB-/-cells displayed significantly decreased AhR mRNA and protein expression, concomitant with loss of AhR target gene expression (Cyp1a1, Cyp1b1, Nqo1). Finally, we found that RelB binds to the Ahr gene at 3 sites to potentially increase its expression via transcriptional induction. These data support that RelB suppresses cigarette smoke-induced apoptosis, potentially by increasing the AhR. Together, these two proteins may comprise an important cell survival signaling pathway that reduces apoptosis upon cigarette smoke exposure.
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Iu
authors.affiliation: Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada.
authors.forename: Michela
authors.initials: M
authors.lastname: Zago
authors.affiliation: Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Rico de Souza
authors.affiliation: Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Manuella
authors.initials: M
authors.lastname: Bouttier
authors.affiliation: Department of Pathology, McGill University, Montreal, Quebec, Canada.
authors.forename: Swati
authors.initials: S
authors.lastname: Pareek
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: White
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada.
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada.
authors.forename: David H
authors.initials: DH
authors.lastname: Eidelman
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montreal, Quebec, Canada; Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Centre (RI MUHC), Montreal, Quebec, Canada. Electronic address: Carolyn.baglole@McGill.ca.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Baglole
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D000073865:Cigarette Smoking / Q000009:adverse effects; D015536:Down-Regulation; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D011485:Protein Binding; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; C497594:Relb protein, mouse; D051841:Transcription Factor RelB; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: Apoptosis; Chromatin immunoprecipitation (ChiP); Chronic obstructive pulmonary disease (COPD); Cigarette smoke