Relationship between I?B? deficiency, NF?B activity and interleukin-8 production in CF human airway epithelial cells

Abstract

Several recent reports have suggested that airway inflammation may precede infection and relate to an endogenous dysregulation of pro-inflammatory cytokines in cystic fibrosis (CF) airways. Evidence suggests that activation of the nuclear factor kappa B (NFkappaB), which regulates the inflammatory gene transcription, depends on the degradation of the inhibitory factor IkappaBalpha. We show that, in in situ human DeltaF508 CF bronchial tissues, inhibitor factor IkappaBalpha is not present in gland cells, although endogenous levels of chemokine IL-8 are high. These data are confirmed by studying cultured CF human bronchial gland cells, in which a lack of cytosolic IkappaBalpha and high levels of activated NFkappaB, concomitant with IL-8 overproduction (a 13-fold increase) are found when compared to non-CF bronchial gland cells. Interestingly, treatment of CF gland cells with the isoflavone genistein, a well known CFTR mutant Cl(-) channel stimulator, results in a significant decrease ( P< 0.001) in IL-8 production down to levels released by non-CF gland cells. The addition of genistein also reverses the effects of lipopolysaccharide (LPS) Pseudomonas-aeruginosa-induced nuclear translocation of NFkappaB by increasing IkappaBalpha protein level (65%) in CF gland cells. Our data indicate that the induction of IkappaBalpha protein in CF airway glandular epithelial cells may be a novel mechanism by which IL-8-mediated lung inflammatory events are markedly reduced in CF patients, at least at the airway glandular level.

Ceramide and sphingosine in pulmonary infections

“…More than 80% of adult cystic fibrosis patients are infected with P. aeruginosa. Furthermore, cystic fibrosis airways are characterized by chronic inflammation with an imbalance between proinflammatory and antiinflammatory cytokines (Inoue et al, 1994;Bonfield et al, 1995;Khan et al, 1995;Tirouvanziam et al, 2000;Venkatakrishnan et al, 2000;Tabary et al, 2001;Oceandy et al, 2002;Verhaeghe et al, 2007). An increase in the concentrations of inflammatory mediators was observed in lungs from aborted fetuses, a finding suggesting that aseptic inflammation occurs very early in cystic fibrosis.…”

Expression levels of FAS are regulated through an evolutionary conserved element in intron 2, which modulates cystic fibrosis disease severity

“…5 Patients are susceptible to bacterial infection by pathogenic organisms such as Pseudomonas aeruginosa, which results in neutrophil-dominated chronic inflammation. 5 The vulnerability of CF patients to infectious disease and the proinflammatory cytokine profile in CF has been based on a perturbed salt-water balance that impairs bacterial clearance, 6 on an altered transcription profile because of a prolonged NF-kB activation 7,8 and recently, on a changed pH of intracellular organelles, which leads to a changed cell membrane composition. 9 On the cellular level, distorted apoptosis was observed in the CF condition: the intestinal epithelial cells of CF individuals showed higher susceptibility to apoptosis, 10 whereas CF respiratory epithelial cells showed delayed apoptosis in response to P. aeruginosa infection.…”

Inflammation of the cystic fibrosis mouse small intestine

“…However, altered electrolyte transport is likely not the whole explanation of CF pathogenesis. A hallmark of CF is inflammation, and in the CF airways, there is evidence that inflammation may be a consequence of loss of CFTR function even in the absence of pathological microbial infection (4,47). It has recently been documented that the intestines of CF patients exhibit inflammation (36,42).…”