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Bacterial stimulation of epithelial G-CSF and GM-CSF expression promotes PMN survival in CF airways

Shahryar Saba1, Grace Soong, Steven Greenberg

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

American Journal of Respiratory Cell and Molecular Biology
|October 25, 2002
PubMed

Insights

Airway epithelial cells in cystic fibrosis (CF) patients over-respond to bacterial infections, promoting survival of neutrophils (PMNs) through cytokine release. This enhanced neutrophil survival contributes to excessive inflammation in CF airways.

Area of Science:

  • Immunology
  • Cell Biology
  • Respiratory Medicine

Background:

  • Airway epithelial cells initiate immune responses to bacterial pathogens by releasing chemokines and cytokines.
  • Cystic Fibrosis (CF) patients exhibit exaggerated inflammatory responses to chronic airway bacterial infections.
  • Nuclear factor-kappaB (NF-κB) signaling is implicated in the epithelial cell response to bacterial pathogens.

Purpose of the Study:

  • To investigate the role of CF airway epithelial cells in modulating polymorphonuclear leukocyte (PMN) survival.
  • To determine if CF airway pathogens induce epithelial cells to produce factors that inhibit PMN apoptosis.
  • To identify specific bacterial components and epithelial cell receptors involved in this process.

Main Methods:

  • Primary human airway epithelial cell cultures (CF and corrected cell lines) were stimulated with Staphylococcus aureus and Pseudomonas aeruginosa.
  • Supernatants from stimulated cells were used to culture isolated human PMNs.
  • PMN apoptosis was assessed, and the role of specific cytokines (G-CSF, GM-CSF) was evaluated using neutralizing antibodies.
  • Bacterial mutants and specific cell surface receptors (asialoGM1) were utilized to probe activation pathways.

Main Results:

  • Epithelial cell supernatants from CF and normal cells exposed to bacteria significantly increased PMN survival (2- to 5-fold).
  • Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by epithelial cells were identified as key mediators of enhanced PMN survival.
  • Cytokine production was triggered by bacterial components like lipoteichoic acid and receptor ligation (asialoGM1), independent of lipopolysaccharide potency.
  • Bacterial mutants affecting lipopolysaccharide and quorum sensing did not impair epithelial cell activation.

Conclusions:

  • CF airway epithelial cells, upon encountering bacteria, release cytokines (G-CSF, GM-CSF) that promote prolonged survival of recruited neutrophils.
  • This mechanism contributes to the excessive and sustained inflammation characteristic of CF lung disease.
  • Targeting these cytokine-mediated survival pathways could offer therapeutic strategies for CF-related inflammation.

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