1 research outputs found
Airway Epithelial Inflammation-induced Endoplasmic Reticulum Ca2+ Store Expansion Is Mediated by X-box Binding Protein-1*
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)/Ca2+ store expansion and
amplified Ca2+-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/Ca2+ 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/Ca2+ store
expansion was then addressed in murine airways challenged with
phosphate-buffered saline or Pseudomonas aeruginosa. P.
aeruginosa-challenged mice exhibited airway epithelial ER/Ca2+
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/Ca2+ 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/Ca2+ 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/Ca2+
store expansion and SMM-induced IL-8 secretion. These findings suggest that,
in inflamed HBE, XBP-1s is responsible for the ER/Ca2+ store
expansion that confers amplification of Ca2+-dependent inflammatory
responses