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Production by Phagocytic Cells1
* Department of Pharmaceutical Sciences and Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman, WA 99164;
Department of Pediatrics and
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
The contribution of environmental factors is important as we consider reasons that underlie differential susceptibility to influenza virus. Aryl hydrocarbon receptor (AhR) activation by the pollutant dioxin during influenza virus infection decreases survival, which correlates with a 4-fold increase in pulmonary IFN-
levels. We report here that the majority of IFN--producing cells in the lung are neutrophils and macrophages not lymphocytes, and elevated IFN- is associated with increased pulmonary inducible NO synthase (iNOS) levels. Moreover, we show that even in the absence of dioxin, infection with influenza virus elicits IFN- production by B cells, 
T cells, CD11c+ cells, macrophages and neutrophils, as well as CD3+ and NK1.1+ cells in the lung. Bone marrow chimeric mice reveal that AhR-mediated events external to hemopoietic cells direct dioxin-enhanced IFN- production. We also show that AhR-mediated increases in IFN- are dependent upon iNOS, but elevated iNOS in lung epithelial cells is not driven by AhR-dependent signals from bone marrow-derived cells. Thus, the lung contains important targets of AhR regulation, which likely influence a novel iNOS-mediated mechanism that controls IFN- production by phagocytic cells. This suggests that AhR activation changes the response of lung parenchymal cells, such that regulatory pathways in the lung are cued to respond inappropriately during infection. These findings also imply that environmental factors may contribute to differential susceptibility to influenza virus and other respiratory pathogens.
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.
1 These studies were supported by grants from the National Institutes of Environmental Health Sciences (R01ES10619 and K02ES012409, to B.P.L.).
2 Address correspondence and reprint requests to Dr. B. Paige Lawrence, Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642. E-mail address: paige_lawrence{at}urmc.rochester.edu
3 Abbreviations used in this paper: AhR, aryl hydrocarbon receptor; AhRE, AhR response element; BAL, bronchoalveolar lavage; iNOS, inducible NO synthase; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TSS, transcription start site; NP, nucleoprotein.
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