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

Activation of the interleukin-1 beta (IL-1 beta) 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-1 beta-associated sputum signature from other inflammation-associated COPD phenotypes. Luminex-multiplex assays were used to study IL-1 beta-mediated signature proteins within airway epithelium, smooth muscle, and vascular endothelial cell cultures. The IL-1 beta-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. Five proteins namely TNF-alpha, GCSF, IL-6, CD-40L, and MIP-1 beta were found to be IL-1 beta-regulated across all donors and cell types. All five of these IL-1 beta-mediated proteins were significantly increased (p < 0.05) in sputum corresponding to AECOPD events showing at least a twofold increase in IL-1 beta (IL-1 beta(+) events, 18 of 35 total events), relative to preceding stable-COPD state. Sputum IL-1 beta 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-1 beta(+) events versus IL-1 beta(-) events. Our findings provide insights into potential markers of IL-1 beta-associated AECOPD, and reaffirm association between IL-1 beta 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-1 beta pathway.