Inflammasome-mediated IL-1β Production in Humans With Cystic Fibrosis

PLoS One. 2012;7(5):e37689. doi: 10.1371/journal.pone.0037689. Epub 2012 May 23.

Abstract

Background: Inflammation and infection are major determinants of disease severity and consequently, the quality of life and outcome for patients with cystic fibrosis (CF). Interleukin-1 beta (IL-1β) is a key inflammatory mediator. Secretion of biologically active IL-1β involves inflammasome-mediated processing. Little is known about the contribution of IL-1β and the inflammasomes in CF inflammatory disease. This study examines inflammasome-mediated IL-1β production in CF bronchial epithelial cell lines and human patients with CF.

Results: Bronchial epithelial cell lines were found to produce negligible amounts of basal or stimulated IL-1β compared to hematopoeitic cells and they did not significantly upregulate caspase-1 activity upon inflammasome stimulation. In contrast, peripheral blood mononuclear cells (PBMCs) from both CF and healthy control subjects produced large amounts of IL-1β and strongly upregulated caspase-1 activity upon inflammasome stimulation. PBMCs from CF patients and controls displayed similar levels of caspase-1 activation and IL-1β production when stimulated with inflammasome activators. This IL-1β production was dependent on NF-κB activity and could be enhanced by priming with LPS. Finally, chemical inhibition of CFTR activity in control PBMCs and THP-1 cells did not significantly alter IL-1β or IL-8 production in response to P. aeruginosa.

Conclusion: Hematopoeitic cells appear to be the predominant source of inflammasome-induced pro-inflammatory IL-1β in CF. PBMCs derived from CF subjects display preserved inflammasome activation and IL-1β secretion in response to the major CF pathogen Pseudomonas aeruginosa. However, our data do not support the hypothesis that increased IL-1β production in CF subjects is due to an intrinsic increase in NF-κB activity through loss of CFTR function.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Caspases / metabolism
  • Cell Line
  • Cystic Fibrosis / complications
  • Cystic Fibrosis / immunology*
  • Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors
  • Epithelial Cells / metabolism
  • Gene Expression Regulation / immunology*
  • Humans
  • Immunoblotting
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Interleukin-1beta / immunology*
  • Interleukin-8 / immunology
  • Interleukin-8 / metabolism
  • Leukocytes, Mononuclear / metabolism
  • NF-kappa B / metabolism
  • Pseudomonas Infections / complications
  • Pseudomonas Infections / immunology*
  • Pseudomonas aeruginosa / immunology*

Substances

  • CFTR protein, human
  • Inflammasomes
  • Interleukin-1beta
  • Interleukin-8
  • NF-kappa B
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Caspases