Cystic fibrosis (CF) is caused by the functional expression defect of the CF transmembrane
conductance regulator (CFTR) chloride channel at the apical plasma membrane. Impaired
bacterial clearance and hyperactive innate immune response are hallmarks of the CF
lung disease, yet the existence of and mechanism accounting for the innate immune
defect that occurs before infection remain controversial. Inducible expression of
either CFTR or the calcium-activated chloride channel TMEM16A attenuated the proinflammatory
cytokines interleukin-6 (IL-6), IL-8, and CXCL1/2 in two human respiratory epithelial
models under air-liquid but not liquid-liquid interface culture. Expression of wild-type
but not the inactive G551D-CFTR indicates that secretion of the chemoattractant IL-8
is inversely proportional to CFTR channel activity in cftr(∆F508/∆F508) immortalized
and primary human bronchial epithelia. Similarly, direct but not P2Y receptor-mediated
activation of TMEM16A attenuates IL-8 secretion in respiratory epithelia. Thus augmented
proinflammatory cytokine secretion caused by defective anion transport at the apical
membrane may contribute to the excessive and persistent lung inflammation in CF and
perhaps in other respiratory diseases associated with documented down-regulation of
CFTR (e.g., chronic obstructive pulmonary disease). Direct pharmacological activation
of TMEM16A offers a potential therapeutic strategy to reduce the inflammation of CF
airway epithelia.
