RRC ID 5567
Author Martino ME, Olsen JC, Fulcher NB, Wolfgang MC, O'Neal WK, Ribeiro CM.
Title Airway epithelial inflammation-induced endoplasmic reticulum Ca2+ store expansion is mediated by X-box binding protein-1.
Journal J. Biol. Chem.
Abstract Inflamed cystic fibrosis (CF) human bronchial epithelia (HBE), or normal HBE exposed to supernatant from mucopurulent material (SMM) from CF airways, exhibit endoplasmic reticulum (ER)/Ca(2+) store expansion and amplified Ca(2+)-mediated inflammation. HBE inflammation triggers an unfolded protein response (UPR) coupled to mRNA splicing of X-box binding protein-1 (XBP-1). Because spliced XBP-1 (XBP-1s) promotes ER expansion in other cellular models, we hypothesized that XBP-1s is responsible for the ER/Ca(2+) store expansion in inflamed HBE. XBP-1s was increased in freshly isolated infected/inflamed CF in comparison with normal HBE. The link between airway epithelial inflammation, XBP-1s, and ER/Ca(2+) store expansion was then addressed in murine airways challenged with phosphate-buffered saline or Pseudomonas aeruginosa. P. aeruginosa-challenged mice exhibited airway epithelial ER/Ca(2+) store expansion, which correlated with airway inflammation. P. aeruginosa-induced airway inflammation triggered XBP-1s in ER stress-activated indicator (ERAI) mice. To evaluate the functional role of XBP-1s in airway inflammation linked to ER/Ca(2+) store expansion, control, XBP-1s, or dominant negative XBP-1 (DN-XBP-1) stably expressing 16HBE14o(-) cell lines were used. Studies with cells transfected with an unfolded protein response element (UPRE) luciferase reporter plasmid confirmed that the UPRE was activated or inhibited by expression of XBP-1s or DN-XBP-1, respectively. Expression of XBP-1s induced ER/Ca(2+) store expansion and potentiated bradykinin-increased interleukin (IL)-8 secretion, whereas expression of DN-XBP-1 inhibited bradykinin-dependent IL-8 secretion. In addition, expression of DN-XBP-1 blunted SMM-induced ER/Ca(2+) store expansion and SMM-induced IL-8 secretion. These findings suggest that, in inflamed HBE, XBP-1s is responsible for the ER/Ca(2+) store expansion that confers amplification of Ca(2+)-dependent inflammatory responses.
Volume 284(22)
Pages 14904-13
Published 2009-5-29
DOI 10.1074/jbc.M809180200
PII M809180200
PMID 19321437
PMC PMC2685672
MeSH Alternative Splicing / genetics Animals Calcium / metabolism* Cell Polarity Cells, Cultured DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Endoplasmic Reticulum / metabolism* Epithelial Cells / metabolism Epithelial Cells / microbiology Epithelial Cells / pathology* Genes, Dominant Genetic Vectors / genetics Humans Inflammation / pathology* Interleukin-8 / metabolism Mice Protein Folding Pseudomonas aeruginosa RNA, Messenger / genetics RNA, Messenger / metabolism Regulatory Factor X Transcription Factors Respiratory System / microbiology Respiratory System / pathology* Signal Transduction Transcription Factors / genetics Transcription Factors / metabolism* X-Box Binding Protein 1
IF 4.106
Times Cited 34