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J Biol Chem. 2008 Oct 24;283(43):28944-57. doi: 10.1074/jbc.M800685200. Epub 2008 Aug 12.

The aryl hydrocarbon receptor attenuates tobacco smoke-induced cyclooxygenase-2 and prostaglandin production in lung fibroblasts through regulation of the NF-kappaB family member RelB.

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  • 1Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.

Abstract

Diseases such as chronic obstructive pulmonary disease and lung cancer caused by cigarette smoke affect millions of people worldwide. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that influences responses to certain environmental pollutants such as tobacco smoke. However, the physiological function(s) of the AhR is unknown. Herein we propose that the physiologic role of the AhR is to limit inflammation. We show that lung fibroblasts from AhR(-/-) mice produce a heightened inflammatory response to cigarette smoke, typified by increased levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs), when compared with wild type (AhR(+/+)) fibroblasts. This response was dependent on AhR expression as transient transfection of an AhR expression plasmid into AhR(-/-) fibroblasts significantly attenuated the smoke-induced COX-2 and PG production, confirming the anti-inflammatory role of the AhR. The AhR can interact with NF-kappaB. However, the heightened inflammatory response observed in AhR(-/-) fibroblasts was not the result of NF-kappaB (p50/p65) activation. Instead it was coupled with a loss of the NF-kappaB family member RelB in AhR(-/-) fibroblasts. Taken together, these studies provide compelling evidence that AhR expression limits proinflammatory COX-2 and PG production by maintaining RelB expression. The association between RelB and AhR may represent a new therapeutic and more selective target with which to combat inflammation-associated diseases.

PMID:
18697742
[PubMed - indexed for MEDLINE]
PMCID:
PMC2570856
Free PMC Article

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