DNA and Actin Bind and Inhibit Interleukin-8 Function in Cystic Fibrosis Sputa

Abstract

Infection of the cystic fibrosis (CF) airways elicits an exaggerated, interleukin-8 (IL-8) mediated, neutrophil inflammatory response. Necrosing neutrophils release DNA and actin into the airways, increasing the viscoelasticity of airway secretions. Mucolytics aim to improve airway clearance by reducing this viscoelasticity. DNase I reduces the viscoelasticity of CF sputum, and a human recombinant form of this enzyme is widely administered to patients with CF. Gelsolin, which cleaves actin polymers, is also known to reduce CF sputum viscosity in vitro, and it has been proposed as a future mucolytic agent. We have shown that the anionic polymers DNA and actin bind and mask immunologic recognition of the basic peptide IL-8 and prevent this chemokine from binding to neutrophil receptors. Reduction of CF sputum viscosity by DNase I or gelsolin in vitro was demonstrated to increase the proportion of free IL-8 and the IL-8-dependent neutrophil chemotactic activity of sputum supernatants. We hypothesize that an electrostatic interaction between polymer and chemokine may limit the inflammatory potential of the latter, but that this interaction may be weakened by polymer cleavage. The potential risk of increased inflammation via this mechanism suggests a caveat should be attendant on treatment of patients with CF with these mucolytic agents.

Interactions between the Aggregatibacter actinomycetemcomitans secretin HofQ and host cytokines indicate a link between natural competence and interleukin-8 uptake

“…Therefore, the interaction between IL-8 and dsDNA, which we demonstrated in this study, might act as a mechanism that combines cytokine uptake with DNA uptake. Our results are consistent with the earlier finding by Perks and Shute [26], who reported the binding of IL-8 to human placental DNA. Interaction between IL-8 and DNA is likely independent of DNA sequence and is dependent on the physicochemical properties of IL-8 and DNA.…”

Anionic poly(amino acid)s dissolve F-actin and DNA bundles, enhance DNase activity, and reduce the viscosity of cystic fibrosis sputum

“…Numerous other polycations may also contribute to bundle stabilization. These include interleukin 8, recently shown to be sequestered by F-actin and DNA in CF (18), and a number of antimicrobial proteins and peptides including lysozyme, as shown in Fig. 1B, defensins, and cathelicidins.…”

Mucin Overproduction in Chronic Inflammatory Lung Disease

“…These gel-forming mucins are primarily responsible for the rheological properties of airway mucus (2). However, in disease states such as CF and chronic bronchitis, polymeric DNA and filamentous actin, two products of leukocyte lysis, contribute greatly to, and are the principal determinants of, the viscoelastic properties of the purulent sputum that is associated with these diseases (3,4). The molecular weights of mucins range between 2×10 6 Da and 40×10 6 Da, and they are composed of 50% to 85% carbohydrate (5)(6)(7).…”