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EFFECTS OF DIESEL EXHAUST ON TLR3 SIGNALING IN RESPIRATORY EPITHELIAL CELLS
Citation:
CIENCEWICKI, J., M. C. MADDEN, AND I. JASPERS. EFFECTS OF DIESEL EXHAUST ON TLR3 SIGNALING IN RESPIRATORY EPITHELIAL CELLS. Presented at Society of Toxicology (SOT), San Diego, LA, March 06 - 10, 2005.
Description:
There are a variety of intrinsic as well as extrinsic factors, such as exposure to air pollution that can affect the pathogenesis of respiratory infections. Diesel exhaust (DE) emissions can significantly contribute to air pollution levels and exposure to DE can alter host defense and immune responses. Double stranded RNA (dsRNA), a by product of viral infections, is a ligand for toll-like receptor 3 (TLR3). In this study, we examined the effects of DE extract (DEE) on dsRNA-induced responses in respiratory epithelial cells. A549 cells were exposed to DEE for 2 hours, subsequently challenged with polyriboinosinic acid:polyribocytidylic acid (poly I:C), a synthetic form of dsRNA, and 24 hours post-exposure analyzed for the expression of IL-6 and IFN-beta. We found that pre-exposure of epithelial cells to DEE significantly increased the expression of IL-6 and IFN-beta in response to poly I:C. Flow cytometric analysis showed that TLR3 is predominantly expressed in the cytoplasm of A549 cells. Exposure to DEE increased TLR3 mRNA levels in these cells. In addition, we examined the expression of the TLR3 adaptor protein Toll/IL-1 receptor domain containing adaptor inducing interferon- beta (TRIF) in response to DEE exposure. We found that exposure to DEE caused an increased expression of TRIF within 3-4 hours post-exposure. Upon activation of TLR3, TRIF associates with TNF receptor-associated factor 6 (TRAF6). TRAF6 is an intracellular signaling protein required for the TLR3-dependent activation of NF-kB and Interferon regulatory factor 3 (IRF3), which regulate the expression of IL-6 and IFN-beta, respectively . Overexpression of a dominant negative version of TRAF6 reversed the effects of DEE on poly I:C-induced IL-6 expression. Taken together these results indicate that exposure of respiratory epithelial cells to DE could potentially alter the response to viral infections by increasing the expression of components involved in the TLR3-dependent signaling cascades.