Interleukin-1, Neutrophil Elastase, and Lipopolysaccharide: Key Pro- Inflammatory Stimuli Regulating Inflammation in Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is a common fatal genetic disease among Caucasians of European descent that is characterized by neutrophil-dominated airway inflammation due to intrinsic cellular abnormalities in the affected epithelial cells. A number of proinflammatory stimuli are responsible for aggravating inflammatory responses in CF bronchial epithelium. Two important host-derived factors with potent proinflammatory effects in CF are interleukin-1 (IL-1) and neutrophil elastase (NE). Microbial-derived factors also have importance in the CF lung, as a significant factor by which pulmonary inflammation is mediated in CF is by Pseudomonas aeruginosa infection. Pseudomonas antigens, including lipopolysaccharide (LPS), can exacerbate pulmonary inflammation in CF by exaggerating proinflammatory gene expression via Toll-like receptor (TLR) activation. TLRs belong to a family of proteins that can recognize and discriminate a diverse array of microbial antigens. Following their activation TLRs transduce intracellular signals that regulate proinflammatory gene expression. Intriguingly IL-1, NE and LPS all utilize the same intracellular signaling pathways to induce their effects. This review will summarise what is known regarding the roles of these important proinflammatory stimuli and their effects on CF epithelium and describe current and novel therapeutic strategies for the treatment of CF lung disease.

CFTR activity and mitochondrial function

“…The role of Interleukin-1, neutrophil elastase and lipopolysaccharide to regulate inflammation in CF has been reviewed by Carroll et al [251]. Studying possible modulators of CFTR expression, we found that IL-1β was able to modulate CFTR expression in a biphasic way.…”

Azithromycin inhibits macrophage interleukin-1β production through inhibition of activator protein-1 in lipopolysaccharide-induced murine pulmonary neutrophilia

“…We have confirmed that azithromycin treatment reduced LPSinduced neutrophil numbers in BALF and IL-1β concentrations in lung tissue. IL-1β is one of the major cytokines involved in the initiation and persistence of inflammation [22] and increased levels of IL-1β have been reported in induced sputum and BALF from patients with neutrophil-dominated inflammatory disorders of the lungs, such as COPD, CF and DPB [23][24][25]. The important role of IL-1β in pulmonary inflammation has been confirmed in several animal studies.…”

Differential epithelial expression of the putative innate immune molecule SPLUNC1 in Cystic Fibrosis

“…Innate immune defences of the lung are significantly impaired in CF as a consequence of a combination of factors, including phenotypic alterations of the airway epithelium, the elevated viscosity, alterations in the ionic strength and pH of the airway lining fluid and the increased levels of inflammatory cells present in the inflamed tissues [ 16 ]. The defects in innate defences become self-sustaining, because the inflammatory cell derived proteases, including neutrophil elastase (NE), released from the abundant mass of recruited cells, specifically degrade many host defence proteins [ 17 ].…”