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J. Biol. Chem., Vol. 283, Issue 43, 28944-28957, October 24, 2008

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The Aryl Hydrocarbon Receptor Attenuates Tobacco Smoke-induced Cyclooxygenase-2 and Prostaglandin Production in Lung Fibroblasts through Regulation of the NF-B Family Member RelB^*

Carolyn J. Baglole, Sanjay B. Maggirwar^¶, Thomas A. Gasiewicz, Thomas H. Thatcher^||, Richard P. Phipps, and Patricia J. Sime^||1

From the Departments of Environmental Medicine and ^¶Microbiology and Immunology, Lung Biology and Disease Program, and ^||Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

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-B. However, the heightened inflammatory response observed in AhR^–/– fibroblasts was not the result of NF-B (p50/p65) activation. Instead it was coupled with a loss of the NF-B 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.

Received for publication, January 25, 2008 , and in revised form, August 11, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants ULIRR024160, T32HL66988, T32ES07026, DE011390, AI071064, ES015775, ES01247, HL075432, and HL088325. This work was also supported by an American Lung Association research training fellowship and a Parker B. Francis fellowship (to C. J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–5.

¹ To whom correspondence should be addressed: Division of Pulmonary and Critical Care Medicine, University of Rochester, 601 Elmwood Ave., Box 692, Rochester, NY 14642. Tel.: 585-275-6526; Fax: 585-273-1114; E-mail: Patricia_Sime{at}urmc.rochester.edu.

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