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Effects of cystic fibrosis transmembrane conductance regulator and F508CFTR on inflammatory response, ER stress, and Ca²⁺ of airway epithelia

Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California

Submitted 11 June 2007 ; accepted in final form 3 September 2007

We tested whether cystic fibrosis (CF) airway epithelia have larger innate immune responses than non-CF or cystic fibrosis transmembrane conductance regulator (CFTR)-corrected cells, perhaps resulting from ER stress due to retention of F508CFTR in the endoplasmic reticulum (ER) and activation of cytosolic Ca²⁺ (Ca_i) and nuclear factor (NF)-B signaling. Adenovirus infections of a human CF (F508/F508) nasal cell line (CF15) provided isogenic comparisons of wild-type (wt) CFTR and F508CFTR. In the absence of bacteria, there were no or only small differences among CF15, CF15-lacZ (-galactosidase-expressing), CF15-wtCFTR (wtCFTR-corrected), and CF15-F508CFTR (to test ER retention of F508CFTR) cells in NF-B activity, interleukin (IL)-8 secretion, Ca_i responses, and ER stress. Non-CF and CF primary cultures of human bronchial epithelial cells (HBE) secreted IL-8 equivalently. Upon infection with Pseudomonas aeruginosa (PA) or flagellin (key activator for airway epithelia), CF15, CF15-lacZ, CF15-wtCFTR, and CF15F508CFTR cells exhibited equal PA binding, NF-B activity, and IL-8 secretion; cells also responded similarly to flagellin when both CFTR (forskolin) and Ca_i signaling (ATP) were activated. CF and non-CF HBE responded similarly to flagellin + ATP. Thapsigargin (Tg, releases ER Ca²⁺) increased flagellin-stimulated NF-B and ER stress similarly in all cells. We conclude that ER stress, Ca_i, and NF-B signaling and IL-8 secretion were unaffected by wt- or F508CFTR in control and during exposure to PA, flagellin, flagellin + ATP, or flagellin + ATP + forskolin. Tg, but not wt- or F508CFTR, triggered ER stress. Previous measurements showing hyperinflammatory responses in CF airway epithelia may have resulted from cell-specific, rather than CFTR- or F508CFTR-specific effects.

nuclear factor-B; interleukin-8; adenovirus; inflammation; endoplasmic reticulum stress; ire1

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