Inflammatory cytokines, particularly the neutrophil chemoattractant IL-8, are elevated in the cystic fibrosis (CF) airway, even in the absence of detectable infection.
This study demonstrates that the defective ASMase pathway in CF is a key contributor to the unabated IL-8 response with P. aeruginosa infection and to the compromised host response failing to eradicate bacteria.
We conclude that enhanced stability of IL-8 mRNA in TTP-deficient CF lung epithelial cells serve to drive the proinflammatory cellular phenotype in the CF lung.
Chronic lung inflammation in cystic fibrosis (CF) is specifically characterized by predominant endobronchial neutrophil infiltrates, colonization by Pseudomonas aeruginosa, and elevated levels of cytokines and chemokines, first of all IL-8.
We measured interleukin-8 (IL-8) and interferon-gamma (IFN-gamma) levels in tears in a group of patients and a group of normal controls to determine if the levels of these cytokines are elevated in CF.
Thus, IL-8 mRNA expression was prolonged after P. aeruginosa stimulation in CF epithelial cells, and this sustained IL-8 expression may contribute to the excessive inflammatory response in CF.
Comparison of cytokine production by airway and blood neutrophils from CF patients also documented distinct profiles: the spontaneous release of IL-8 and IL-1ra by airway neutrophils was significantly higher than that from blood neutrophils.
Treatment with IL-10 suppressed IL-8 and RANTES gene expression in both non-CF and CF bronchial epithelial cells was associated with a reduced expression of I(k)B (IKK) alpha/beta kinases, particularly for IKKalpha which is greater expressed in CF bronchial epithelial cells, and resulting in reduced NF-kappaB activation.
Ligation of the asialoGM1 receptor with specific antibody induced greater IL-8 expression in IB3 cells than C-38 cells, consistent with the greater density of asialoGM1 receptors in CF phenotype cells.
The increased content of pro-inflammation cytokines such as interleukin-8 (IL-8) suggest that, before infection, airway inflammation occurs very early in CF.
Although increased ICAM-1 and IL-8 expression are observed in some CF airway epithelial cell models, many CF cells do not exhibit significant dysregulation of these important inflammatory genes.
In human peripheral blood monocyte-derived macrophages the peptides caused production of interleukin-8, a proinflammatory chemokine typically present at excessively high levels in the CF lung.
To evaluate the expression of beta defensin (HBD-1 and HBD-2) mRNA and the presence of inflammatory markers (percentage of neutrophils and IL-8 mRNA expression) in CF and non-CF nasal mucosa.
IL-8 production is controlled by genes from the TNF-alphaR/NFkappaB pathway, and it is possible that the CF phenotype is due to dysfunction of genes from this pathway.
Repair of both defective channels and high IL-8 secretion can also be effected by treatment with the candidate CF drug CPX, which is in clinical trials in CF patients.