A Sputum Proteomic Signature That Associates with Increased IL-1β Levels and Bacterial Exacerbations of COPD

Lung. 2016 Jun;194(3):363-9. doi: 10.1007/s00408-016-9877-0. Epub 2016 Apr 15.

Abstract

Purpose: Activation of the interleukin-1β (IL-1β) signaling pathway has been implicated in COPD, but the proportion of COPD subjects whose disease is principally driven by activation of this pathway is poorly understood. In this study, we sought to differentiate an IL-1β-associated sputum signature from other inflammation-associated COPD phenotypes.

Methods: Luminex-multiplex assays were used to study IL-1β-mediated signature proteins within airway epithelium, smooth muscle, and vascular endothelial cell cultures. The IL-1β-mediated signature was tested in a longitudinal study comprising of 35 paired stable-COPD and acute exacerbation (AECOPD) sputum samples. The presence of respiratory pathogens (H. influenzae, M. catarrhalis, S. pneumoniae, and P. aeruginosa) was evaluated by sputum cultures.

Results: Five proteins namely TNF-α, GCSF, IL-6, CD-40L, and MIP-1β were found to be IL-1β-regulated across all donors and cell types. All five of these IL-1β-mediated proteins were significantly increased (p < 0.05) in sputum corresponding to AECOPD events showing at least a twofold increase in IL-1β (IL-1β(+) events, 18 of 35 total events), relative to preceding stable-COPD state. Sputum IL-1β levels showed no significant association (p > 0.05, spearman) with known markers of other major COPD inflammation phenotypes. In addition, there was a significant association with bacterial presence in sputum culture with an odds ratio of 9 (95 % CI 1.56, 51.9) in IL-1β(+) events versus IL-1β(-) events.

Conclusion: Our findings provide insights into potential markers of IL-1β-associated AECOPD, and reaffirm association between IL-1β pathway activation and airway bacterial infection in COPD. Taken together, our findings could help identify COPD patient subsets who may benefit from therapies targeting IL-1β pathway.

Keywords: Airway inflammation; COPD; IL-1β; Sputum biomarkers.

MeSH terms

  • Aged
  • Aged, 80 and over
  • CD40 Ligand / metabolism
  • Cells, Cultured
  • Chemokine CCL4 / metabolism
  • Disease Progression
  • Endothelial Cells / metabolism
  • Female
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Haemophilus influenzae / isolation & purification
  • Humans
  • Interleukin-1beta / metabolism*
  • Interleukin-6 / metabolism
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Moraxella catarrhalis / isolation & purification
  • Muscle, Smooth / cytology
  • Muscle, Smooth / metabolism
  • Proteome
  • Pseudomonas aeruginosa / isolation & purification
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Pulmonary Disease, Chronic Obstructive / microbiology*
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism
  • Signal Transduction
  • Sputum / metabolism*
  • Sputum / microbiology*
  • Streptococcus pneumoniae / isolation & purification
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Chemokine CCL4
  • Interleukin-1beta
  • Interleukin-6
  • Proteome
  • Tumor Necrosis Factor-alpha
  • Granulocyte Colony-Stimulating Factor
  • CD40 Ligand