Scientists report that immune signaling protein interleukin-26 (IL-26) is increased among chronic smokers with lung disease and that this finding offers new opportunities for developing more effective therapy for these patients. 

Chronic tobacco smokers have a substantially increased rate of chronic obstructive pulmonary disease (COPD), chronic bronchitis, and bacterial lung infections, and these disorders respond poorly to currently available therapies. This is thought to be associated with the accumulation of neutrophils in their airways.

Karlhans Fru Che, Ph.D., and Anders Lindén, M.D., Ph.D., from the Karolinska Institute, led a team of researchers from universities in Sweden and Finland to investigate why chronic smokers with lung disease have such high levels of neutrophils. They found that levels of IL-26 are higher in the lungs of these patients. The molecule is thought to be a proinflammatory neutrophil mobilizer and has previously been found at high concentrations in patients with autoimmune conditions, such as Crohn's disease and rheumatoid arthritis, as well as chronic infections, such as hepatitis C, all of which are also associated with excessive accumulation of neutrophils. 

The team published its study (“The Neutrophil-Mobilizing Cytokine Interleukin-26 in the Airways of Long-Term Tobacco Smokers”) in Clinical Science.

“Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail [bronchial] wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor κ B (NF-κB); a proven regulator of IL-26 production” write the investigators. 

“In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-κB and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples ) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.”

“Previous research shows that the immunological alterations in the airways of chronic smokers, with or without COPD and chronic bronchitis, include an excessive accumulation of neutrophils in parallel with an enhanced frequency of bacterial infections. Our findings show for the first time that IL-26 may be involved in the mobilization of neutrophils and in the response to bacterial colonization in chronic smokers with or without COPD,” said Dr. Che.

He and his colleagues looked at the effects of water-soluble tobacco smoke components on human lung cells and found that the exposure triggered the cells to start producing higher than normal amounts of IL-26. They also found increased amounts of other proinflammatory proteins in the tobacco-exposed cells, such as NF-κB, which appeared to increase in response to increased IL-26 concentrations. Abnormal regulation of NF-κB has been linked to autoimmune disease, infections, and cancer in other research. 

While the researchers found that IL-26 levels were higher than normal in the chronic smokers, regardless of whether they had clinically stable COPD, they also found that those who did have chronic bronchitis or growth of bacteria had higher levels of IL-26 than those who did not. Moreover, the chronic smokers with exacerbations of COPD had higher levels of IL-26 than those with clinically stable COPD. 

“In a previous study, we showed that IL-26 is released by a bacterial compound in healthy human airways and that it enhances the chemotactic response of neutrophils. By now showing that IL-26 is involved in the excessive mobilization of neutrophils in chronic smokers with or without COPD and chronic bronchitis, we strengthen the evidence that this cytokine bears potential as a target for monitoring of and therapeutic intervention in airway disorders characterized by neutrophilic inflammation. However, more studies are needed to improve the understanding of the more precise mechanisms of action of IL-26 before this cytokine can be targeted in clinical trials,” explained Dr. Che.

The researchers believe their work indicates that IL-26 is a promising target to monitor lung disease risk or burden in chronic smokers and that this knowledge could help develop more effective therapies for this difficult-to-treat group in the future. However, they acknowledge that further work is needed to confirm this. 

“Our findings position IL-26 as a promising molecular target that may help improve our understanding of the pathogenic mechanisms behind pulmonary morbidities in chronic tobacco smokers. This knowledge may prove useful for developing new diagnostic tools and criteria as well as for monitoring of disease over time. In a longer perspective, this knowledge may even prove useful for developing new therapy against tobacco-related lung diseases such as COPD, chronic bronchitis, and, perhaps, against repeated bacterial infections in the airways,” noted Dr. Che.

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