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This Article Full Text Full Text (PDF) All Versions of this Article: 290/6/L1154    most recent 00318.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Ciencewicki, J. Articles by Jaspers, I. Search for Related Content PubMed PubMed Citation Articles by Ciencewicki, J. Articles by Jaspers, I.

Diesel exhaust enhances virus- and poly(I:C)-induced Toll-like receptor 3 expression and signaling in respiratory epithelial cells

¹Curriculum of Toxicology, ²Center for Environmental Medicine, Asthma, and Lung Biology, ³Department of Pediatrics, and ⁴US EPA-Human Studies Division, University of North Carolina, Chapel Hill, North Carolina

Submitted 19 July 2005 ; accepted in final form 4 January 2006

Prior exposure of respiratory epithelial cells to an aqueous-trapped solution of diesel exhaust (DE_as) enhances the susceptibility to influenza infections. Here, we examined the effect of DE_as on the Toll-like receptor 3 (TLR3) pathway, which is responsible for the recognition of and response to viruses and double-stranded RNA. Flow cytometric and confocal microscopy analyses showed that TLR3 is predominantly expressed in the cytoplasm of respiratory epithelial cells. To examine the effect of DE on TLR3 expression and function, differentiated human bronchial or nasal epithelial cells as well as A549 cells were exposed to DE_as and then infected with influenza A or treated with polyriboinosinic acid-polyribocytidylic acid [poly(I:C)], a synthetic form of double-stranded RNA. Exposure to DE_as before infection with influenza or stimulation with poly(I:C) significantly upregulated the expression of TLR3. Additionally, preexposure to DE_as significantly increased the poly(I:C)-induced expression of IL-6. Overexpression of a dominant-negative mutant form of TNF receptor-associated factor 6 reversed the effects of DE_as on poly(I:C)-induced IL-6 expression, suggesting that the response was TLR3 dependent. Similarly, preexposure to DE_as significantly increased nuclear levels of interferon regulatory factor 3 and the expression of IFN- in response to poly(I:C). Pretreatment with wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, was able to abate the effect of DE_as on poly(I:C)-induced IFN- expression. Together, these results indicate that exposure of respiratory epithelial cells to DE_as could potentially alter the response to viral infections by increasing the expression and function of TLR3.

epithelial cells; Toll-like receptors; in vitro; respiratory virus

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