RelB attenuates cigarette smoke extract-induced apoptosis in association with transcriptional regulation of the aryl hydrocarbon receptor
| Autor: | Matthew Iu, Angela Rico de Souza, Qutayba Hamid, John H. White, Swati Pareek, David H. Eidelman, Carolyn J. Baglole, Manuella Bouttier, Michela Zago |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Transcription Genetic CYP1B1 SOD2 Poly (ADP-Ribose) Polymerase-1 Down-Regulation Apoptosis Biology Biochemistry Cigarette Smoking 03 medical and health sciences Mice Pulmonary Disease Chronic Obstructive 0302 clinical medicine Physiology (medical) Animals Humans Transcription factor 3' Untranslated Regions Lung Cells Cultured chemistry.chemical_classification Mice Knockout Reactive oxygen species RELB Transcription Factor RelB respiratory system Fibroblasts Aryl hydrocarbon receptor 3. Good health Mice Inbred C57BL 030104 developmental biology chemistry Receptors Aryl Hydrocarbon 030220 oncology & carcinogenesis biology.protein Cancer research Signal transduction Reactive Oxygen Species Protein Binding Signal Transduction |
| Zdroj: | Free radical biologymedicine. 108 |
| ISSN: | 1873-4596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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