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

Abstract

In the clinical setting, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene enhance the inflammatory response in the lung to Pseudomonas aeruginosa ( P. aeruginosa ) infection. However, studies on human airway epithelial cells in vitro have produced conflicting results regarding the effect of mutations in CFTR on the inflammatory response to P. aeruginosa, and there are no comprehensive studies evaluating the effect of P. aeruginosa on the inflammatory response in airway epithelial cells with the ΔF508/ΔF508 genotype and their matched CF cell line rescued with wild-type (wt)-CFTR. CFBE41o- cells (ΔF508/ΔF508) and CFBE41o- cells complemented with wt-CFTR (CFBE-wt-CFTR) have been used extensively as an experimental model to study CF. Thus the goal of this study was to examine the effect of P. aeruginosa on gene expression and cytokine/chemokine production in this pair of cells. P. aeruginosa elicited a more robust increase in cytokine and chemokine expression (e.g., IL-8, CXCL1, CXCL2 and TNF-α) in CFBE-wt-CFTR cells compared with CFBE-ΔF508-CFTR cells. These results demonstrate that CFBE41o- cells complemented with wt-CFTR mount a more robust inflammatory response to P. aeruginosa than CFBE41o-ΔF508/ΔF508-CFTR cells. 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 the lungs of patients with CF have abundant levels of proinflammatory cytokines and chemokines, because the lung is populated by immune cells and epithelial cells there is no way to know, a priori, whether airway epithelial cells in the CF lung in vivo are hyperinflammatory in response to P. aeruginosa compared with non-CF lung epithelial cells. Thus studies on human airway epithelial cell lines and primary cells in vitro that propose to examine the effect of mutations in CFTR on the inflammatory response to P. aeruginosa have uncertain clinical significance with regard to CF.

CFTR Controls the Activity of NF-κB by Enhancing the Degradation of TRADD

“…Elevated IL-8 secretion by these CF cells can be corrected to near wildtype levels by rescue with Wt CFTR [14]. However, this is not a universal finding, since other groups have reported that there is either no difference, or less cytokine release, when comparing cells containing mutant CFTR compared to cells expressing Wt CFTR [15][16][17][18][19]. Nonetheless, it is widely accepted that patients with CF have a more robust inflammatory response to bacterial infection compared to non-CF patients with similar infections [20][21][22][23].…”

Mechanisms of phagocytosis and host clearance ofPseudomonas aeruginosa

“…Nonopsonic phagocytosis is a crucial mechanism for host control during the initial stages of infection, and mouse models indicate that this process may dictate colonization efficiency at the onset of P. aeruginosa challenge (4). Whereas recent reports and reviews have detailed various other components of P. aeruginosa respiratory disease, such as pulmonary edema, humoral immunity, and therapeutic avenues (10,16,20,31,32,46,51,61,73,88,96,102,110,122), this review will spotlight the current state of knowledge in nonopsonic phagocytic recognition and response mechanisms to P.…”

CFTR and lung homeostasis

“…Unexpectedly, they found that WT CFTRexpressing CFBE41oϪ cells had a greater response to P. aeruginosa infection than ⌬F508 CFTR-expressing CFBE41oϪ cells as monitored by IL-8 and TNF-␣ expression (33). The authors suggest that, given these results, studies on human airway cell lines and primary cells that examine how CFTR mutations affect the inflammatory response to P. aeruginosa infections may not be clinically relevant (33).…”