Impaired expression of hypoxia-inducible factor-1α in cystic fibrosis airway epithelial cells – A role for HIF-1 in the pathophysiology of CF?

Abstract

The continuous infection-inflammation cycle plays a crucial role in the progression of cystic fibrosis (CF) disease. This noxious loop can be aggravated by a reduced partial pressure of oxygen in the blood, hypoxemia, present in CF patients. These interconnected factors, hypoxia, inflammation and infection, by stabilizing the hypoxia-inducible factor-1α (HIF-1α) protein subunit, are able to activate the transcription factor HIF-1. To date, data investigating the potential role of HIF-1 in CF are scarce. Our results demonstrated that HIF-1α protein expression was altered in CF-affected compared to CFTR-corrected airway epithelial cells in unsimulated and simulated hypoxic conditions. In contrast, when CF-affected cells were infected with Pseudomonas aeruginosa, HIF-1α was more stabilized compared to CFTR-corrected cells. As HIF-1 is linked with an efficient immune response and pulmonary complications in cystic fibrosis, this difference in HIF-1α protein levels could have an impact in the CF pathology and the persistence of P. aeruginosa infection.

Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response

“…For this, IB3-1 airway epithelial cells were infected with P. aeruginosa strain PAO1 in the absence or the presence of CDCA. Infection by PAO1 for 3 h at an MOI of 25:1 led to HIF-1␣ protein stabilization in IB3-1 airway epithelial cells, as previously published (31) (Fig. 6B).…”

“…Since then, several other signals have been described. More recently, infections with human pathogens (25)(26)(27)(28)(29)(30), including P. aeruginosa (30)(31)(32), and chronic inflammation, e.g., rheumatoid arthritis (21), have been shown to stabilize HIF-1␣ in immune and/or epithelial cells. Consequently, HIF-1 induces genes involved in the host immune response, such as antimicrobial peptides, nitric oxide, and several cytokines, including TNF-␣, which help in the fight against and limit the spread of infection (30).…”

Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1α Degradation

“…A549 (ATCC CCL-185) is a lung adenocarcinoma epithelial cell line derived for a patient with a lung carcinoma. IB3-1 and S9 cells were cultured using LHC-8 medium (Invitrogen) as previously described (26). CFTE and A549 cells were cultured using minimal essential medium (MEM) M7278 supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 units/ml penicillin, and 100 g/ml streptomycin.…”

“…To date, a number of Enterobacteriaceae species (18), including Escherichia coli (3), Chlamydia (44,49), Pseudomonas aeruginosa (26,40,48), and group A Streptococcus (39,40), have all been shown to stabilize HIF-1␣ in both immune and epithelial cells. Stabilization of HIF-1␣ and subsequent HIF-1 activation promote the release of antimicrobial peptides such as cathelicidins and granule proteases and stimulate the production of nitric oxide and tumor necrosis factor alpha (TNF-␣) (34,40).…”

“…As to date, bacteria and bacterial compounds have been shown to lead to HIF-1␣ protein accumulation (3,15,18,25,26,39,40,44,49,55), it was therefore unexpected to find that P. aeruginosa AQ signaling molecules suppressed HIF-1␣ protein levels. Destabilization occurred through degradation by the 26S proteasome machinery and resulted in modulation of the HIF-1 target gene HKII.…”