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Cystic fibrosis pathogens activate Ca2+-dependent mitogen-activated protein kinase signaling pathways in airway

A J Ratner1, R Bryan, A Weber

  • 1College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.

The Journal of Biological Chemistry
|March 30, 2001
PubMed

Insights

Cystic fibrosis airway inflammation involves interleukin-8 (IL-8) release. Bacteria bind to specific cell receptors, triggering a common pathway for IL-8 expression and inflammation in lung disease.

Area of Science:

  • Pulmonary Medicine
  • Microbiology
  • Cell Biology

Background:

  • Cystic fibrosis lung disease is characterized by inflammation driven by polymorphonuclear leukocytes, often initiated by bacterial infections.
  • Respiratory epithelial cells release interleukin-8 (IL-8), a key inflammatory chemokine, upon binding to asialylated glycolipid receptors.
  • These receptors are upregulated on damaged, regenerating, or CFTR-mutated cells, and are recognized by common cystic fibrosis pathogens like Pseudomonas aeruginosa and Staphylococcus aureus.

Purpose of the Study:

  • To investigate if diverse bacteria utilize a common epithelial signaling pathway to induce IL-8 expression in cystic fibrosis.
  • To determine the role of asialylated glycolipid receptors in mediating bacterial-induced airway inflammation.

Main Methods:

  • Utilized 1HAEo- airway epithelial cells stimulated with specific bacterial strains (P. aeruginosa PAO1, S. aureus RN6390) and mutants.
  • Measured intracellular calcium ([Ca(2+)](i)) increases, activation of p38 and ERK1/2 mitogen-activated protein kinase (MAPK) pathways, and NF-kappaB activation.
  • Investigated the role of asialoGM1 receptor ligation and thapsigargin-induced calcium release, comparing with P. aeruginosa lipopolysaccharide stimulation.

Main Results:

  • P. aeruginosa PAO1 and S. aureus RN6390, but not their respective mutants, induced [Ca(2+)](i) increases in airway epithelial cells.
  • This calcium flux activated p38 and ERK1/2 MAPK signaling, leading to NF-kappaB activation and subsequent IL-8 expression.
  • Ligation of asialoGM1 receptors or calcium release activated the pathway, while bacterial lipopolysaccharide did not; rapid epithelial activation suggested it preceded bacterial invasion.

Conclusions:

  • Recognition of asialylated glycolipid receptors on airway epithelial cells represents a conserved pathway for both Gram-positive and Gram-negative bacteria to initiate airway inflammation.
  • This common pathway contributes to the polymorphonuclear leukocyte-dominated inflammation observed in cystic fibrosis lung disease.
  • Targeting this receptor-mediated signaling could offer a novel therapeutic strategy for managing cystic fibrosis-related pulmonary exacerbations.

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