The NF-κB family member RelB regulates microRNA miR-146a to suppress cigarette smoke-induced COX-2 protein expression in lung fibroblasts.
Diseases due to cigarette smoke exposure, including chronic obstructive pulmonary disease (COPD) and lung cancer, are associated with chronic inflammation typified by the increased expression of cyclooxygenase-2 (COX-2) protein. RelB is an NF-κB family member that suppresses cigarette smoke induction of COX-2 through an unknown mechanism. The ability of RelB to regulate COX-2 expression may be via miR-146a, a miRNA that attenuates COX-2 in lung fibroblasts. In this study we tested whether RelB attenuation of cigarette smoke-induced COX-2 protein is due to miR-146a. Utilizing pulmonary fibroblasts deficient in RelB expression, together with siRNA knock-down of RelB, we show the essential role of RelB in diminishing smoke-induced COX-2 protein expression despite robust activation of the canonical NF-κB pathway and subsequent induction of Cox-2 mRNA. RelB did not regulate COX-2 protein expression at the level of mRNA stability. Basal levels of miR-146a were significantly lower in Relb-deficient cells and cigarette smoke increased miR-146a expression only in Relb-expressing cells. Inhibition of miR-146a had no effects on Relb expression or induction of Cox-2 mRNA by cigarette smoke but significantly increased COX-2 protein. These data highlight the potential of a RelB-miR-146a axis as a novel regulatory pathway that attenuates inflammation in response to respiratory toxicants.
Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
Michela
M
Zago
Research Institute of the McGill University Health Centre, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
Angela
A
Rico de Souza
Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
Emelia
E
Hecht
Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada; Research Institute of the McGill University Health Centre, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
Simon
S
Rousseau
Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada; Research Institute of the McGill University Health Centre, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
Qutayba
Q
Hamid
Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada; Research Institute of the McGill University Health Centre, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
David H
DH
Eidelman
Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada; Research Institute of the McGill University Health Centre, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada. Electronic address: Carolyn.baglole@McGill.ca.
Carolyn J
CJ
Baglole
D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000235:genetics; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D051841:Transcription Factor RelB / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D012333:RNA, Messenger; C497594:Relb protein, mouse; D012906:Smoke; D051841:Transcription Factor RelB; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
Chronic obstructive pulmonary disease; Cigarette smoke; Cyclooxygenase-2; Fibroblast; MicroRNA; NF-κB