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

• Published in: American journal of physiology. Lung cellular and molecular physiology 2006-06, Vol.290 (6), p.L1154-L1163
• Main Authors: Ciencewicki, Jonathan, Brighton, Luisa, Wu, Wei-Dong, Madden, Michael, Jaspers, Ilona
• Format: Article
• Language: English
• Subjects: Cell Line; Gene Expression Regulation - drug effects; Humans; Poly I-C - pharmacology; Respiratory Mucosa - drug effects; Respiratory Mucosa - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Toll-Like Receptor 3 - genetics; Vehicle Emissions - adverse effects; Virus Diseases - epidemiology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00318.2005

1 Curriculum of Toxicology, 2 Center for Environmental Medicine, Asthma, and Lung Biology, 3 Department of Pediatrics, and 4 US 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 Address for reprint requests and other correspondence: I. Jaspers, Univ. of North Carolina, CB# 7310, 104 Mason Farm Rd., Chapel Hill, NC 27599 (e-mail: Ilona_jaspers{at}med.unc.edu )