Synergism Between Interleukin (IL)-17 and Toll-like Receptor 2 and 4 Signals to Induce IL-8 Expression in Cystic Fibrosis Airway Epithelial Cells

Abstract

Cystic fibrosis (CF) is the most common lethal inherited disorder and is caused by mutations in the gene encoding the CF transmembrane regulator (CFTR). The CF lung expresses a profound proinflammatory phenotype that appears to be related to a constitutive hypersecretion of interleukin (IL)-8 from airway epithelial cells in response to microbial infection. Since overproduction of IL-8 in CF contributes to massive bronchial infiltrates of neutrophils, identification of the pathways underlying IL-8 induction could provide novel drug targets for treatment of neutro-phil-dominated inflammatory diseases such as CF. Here, we show that IL-17A synergistically increases IL-8 production induced by a toll-like receptor (TLR) 2 agonist, peptidoglycan (PGN), or TLR4 agonist, lipopolysaccharide (LPS), in a human CF bronchial epithelial cell line ( CFBE41o-). A strong synergism was also observed in primary human CF bronchial epithelial cells, but not in human non-CF cell lines and primary cells. Notably, despite the induction of nuclear factor-κB and MAP kinases during TLR2 or TLR4 activation in CFBE41o-, IL-17A-dependent synergism appears to be the result of enhanced PGN- or LPS-induced phosphorylation of p38. Taken together, these studies provide evidence that IL-17A is a critical factor in increasing IL-8 expression in bacteria-infected CF airways via a pathway that regulates p38 phosphorylation.

IL-17A and Th17 Cells in Lung Inflammation: An Update on the Role of Th17 Cell Differentiation and IL-17R Signaling in Host Defense against Infection

“…In the literature, it has been reported that TNF- α , IL-1 β , IL-22, Oncostatin M, IFN γ , BAFF, and CD40L can all synergize with IL-17A to upregulate IL-17A target genes or their respective target genes [129, 139, 145–147]. In addition, IL-17A also synergizes with TLR2 and TLR4 ligands to increase IL-8 production in a human cystic fibrosis bronchial epithelial cell lines [148]. In an in vivo context, this may be where IL-17A induces its most potent effects, within the cytokine milieu of an inflammatory setting to further potentiate the inflammatory response.…”

The DsbA-L gene is associated with respiratory function of the elderly via its adiponectin multimeric or antioxidant properties

“…Cell culture. 16HBE14o-cells were generated as reported previously 34 and grown in fibronectin/vitrogen/ BSA-coated flask in MEM (Invitrogen, Inc., Carlsbad, CA, USA) 35 . These cells were maintained in MEM supplemented with 10% fetal bovine serum, 2% penicillin/streptomycin.…”

Current Concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung Disease

“…Specific cell source, modulation of culture conditions and/or specific stimuli might explain these discrepancies. A strong synergism between TLR2/PGN- and TLR4/LPS-mediated IL-8 production and IL17A was found in human bronchial epithelial cell lines [126]. Recently, genotyping of TLR polymorphisms revealed that CF airway epithelial cells are homozygous for TLR1 SNP 1602S and possess a diminished innate immune response towards Mycobacterium abscessus infection .…”