Dysregulated interleukin-8 secretion and NF-κB activity in human cystic fibrosis nasal epithelial cells

Abstract

CF respiratory epithelial cells exhibit a basal dysregulated production of IL-8 that partially correlates to enhanced NF-kappaB activity. Our data corroborate the hypothesis of a basal exaggerated inflammatory response in the CF respiratory epithelium.

Newborn Cystic Fibrosis Pigs Have a Blunted Early Response to an Inflammatory Stimulus

“…These transcriptional differences were manifest in the absence of phagocytes or other immune cells, suggesting that airway epithelia drove the transcriptional responses observed in vivo following the inflammatory stimulus. This is consistent with literature implicating CF airway epithelia in the dysregulated inflammatory and host defense responses that characterize the CF lung (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

“…Our results differ somewhat from many earlier studies suggesting that CF airway epithelia are intrinsically proinflammatory or hyperinflammatory. Reports describe overproduction of proinflammatory mediators, particularly IL-8, in CF cell lines, primary CF airway cells, and subepithelial spaces of human fetal CF airway grafts (17,19,22,24,(27)(28)(29)(30). Studies using CF mice report altered regulation of several inflammatory mediators (23,31,32), and enhanced proinflammatory cytokine production in response to pulmonary Pseudomonas aeruginosa exposure compared with wild-type counterparts (33).…”

Does the ΔF508-CFTR mutation induce a proinflammatory response in human airway epithelial cells?

“…We report that P. aeruginosa elicited a more robust increase in cytokine and chemokine expression (e.g., IL-8, CXCL1, CXCL2, and TNF-␣) in CFBE-wt-CFTR cells compared with CFBE-⌬F508-CFTR cells. These data add to a growing body of evidence revealing that the inflammatory response of human airway epithelial cells expressing wt-CFTR and ⌬F508-CFTR to P. aeruginosa is model dependent, even when considering matched cell lines and human airway epithelial cells in primary culture (4,6,8,16,18,22,26,28,31,37,39,41). Taken together with other published studies, our data demonstrate that there is no compelling evidence to support the view that mutations in CFTR induce a hyperinflammatory response in human airway epithelial cells in vivo.…”

“…Although it is generally assumed that CF airway epithelial cells are hyperinflammatory in response to P. aeruginosa compared with non-CF airway epithelial cells, human CF airway cells in culture often fail to show a hyperinflammatory phenotype compared with airway epithelial cells expressing wild-type (wt)-CFTR (16,21,35). Indeed, one-third of published studies reveal that CF airway cells elaborate a more robust increase in IL-8 production than non-CF cells in response to P. aeruginosa (28,37,39,41), one-third report no difference (4,6,8,16,26), and one-third actually report that wt-CFTR cells release more IL-8 than CF cells in response to P. aeruginosa (18,22,31). Moreover, because the lungs during infection with P. aeruginosa contain immune cells that, like airway epithelial cells, produce cytokines and chemokines, it is not possible to determine whether the cytokines and chemokines in vivo originate from immune cells and/or airway epithelial cells.…”

Hyperinflammation in airways of cystic fibrosis patients: what’s new?

“…The airway epithelium is an important source of chemokine IL-8 and is the principal neutrophil chemoattractant in the CF lung [16]. During the past decade, cell culture systems using primary human bronchial epithelial cells and respiratory cell lines have revealed that CF cells exhibit enhanced proinflammatory signaling compared with non-CF cells [17][18][19][20][21][22][23]. This intrinsic inflammation was mainly characterized by an increased level of inflammatory mediators (e.g., IL-8 and IL-6) compared with non-CF bronchial epithelial cells, either in the absence [19,21,24] or presence of bacterial stimulation [25][26][27][28].…”