| Autor: |
Zago M; Department of Medicine, McGill University, Montreal, Quebec, Canada., Sheridan JA; Department of Medicine, McGill University, Montreal, Quebec, Canada., Traboulsi H; Department of Medicine, McGill University, Montreal, Quebec, Canada., Hecht E; Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada., Zhang Y; Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada., Guerrina N; Department of Pathology McGill University, Montreal, Quebec, Canada., Matthews J; Department of Nutrition, University of Oslo, Oslo, Norway., Nair P; Department of Medicine, McMaster University, Hamilton, ON, Canada., Eidelman DH; Department of Medicine, McGill University, Montreal, Quebec, Canada.; Department of Pathology McGill University, Montreal, Quebec, Canada., Hamid Q; Department of Medicine, McGill University, Montreal, Quebec, Canada.; Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.; Department of Pathology McGill University, Montreal, Quebec, Canada., Baglole CJ; Department of Medicine, McGill University, Montreal, Quebec, Canada.; Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada.; Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.; Department of Pathology McGill University, Montreal, Quebec, Canada. |
| Abstrakt: |
Heightened inflammation, including expression of COX-2, is associated with chronic obstructive pulmonary disease (COPD) pathogenesis. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is reduced in COPD-derived lung fibroblasts. The AhR also suppresses COX-2 in response to cigarette smoke, the main risk factor for COPD, by destabilizing the Cox-2 transcript by mechanisms that may involve the regulation of microRNA (miRNA). Whether reduced AhR expression is responsible for heightened COX-2 in COPD is not known. Here, we investigated the expression of COX-2 as well as the expression of miR-146a, a miRNA known to regulate COX-2 levels, in primary lung fibroblasts derived from non-smokers (Normal) and smokers (At Risk) with and without COPD. To confirm the involvement of the AhR, AhR knock-down via siRNA in Normal lung fibroblasts and MLE-12 cells was employed as were A549-AhRko cells. Basal expression of COX-2 protein was higher in COPD lung fibroblasts compared to Normal or Smoker fibroblasts but there was no difference in Cox-2 mRNA. Knockdown of AhR in lung structural cells increased COX-2 protein by stabilizing the Cox-2 transcript. There was less induction of miR-146a in COPD-derived lung fibroblasts but this was not due to the AhR. Instead, we found that RelB, an NF-κB protein, was required for transcriptional induction of both Cox-2 and miR-146a. Therefore, we conclude that the AhR controls COX-2 protein via mRNA stability by a mechanism independent of miR-146a. Low levels of the AhR may therefore contribute to the heightened inflammation common in COPD patients. |
