Abstract
Nucleotides have effects on immune cells which are complex but generally proinflammatory, and have been suggested to play a role in smoking-related lung diseases. However, there have been no studies directly measuring functional responses to nucleotides in human lungs taken from smokers. We used fragments of post mortem human lung from smokers and non-smokers, incubated them with a range of nucleotides (4–1000 µM) in the presence of lipopolysaccharide (LPS; 10 µg/ml) for 24 hours and measured cytokines (IL-1β, IFNγ, IL-17, TNFα, IL-6, IL-8, IL-2 and IL-10) in the supernatants using multiplex immunoassays. Although the basal cytokine levels in the smokers were generally higher in the smokers than the non-smokers, there were no significant differences in either the basal release or the LPS-stimulated release of any of the cytokines when lungs from smokers and non-smokers were compared. There were no significant effects of ATP, ADP, AMP, UTP, α,β-methylene-ATP, P1, P4-diATP, 2-methylthio-ATP or Bz-ATP on the release of cytokines from the lungs. However, the stable ATP analogue ATPγS increased the release of IL-1β and IFNγ, and the effect was greatly increased in lungs from smokers. In non-smokers but not in smokers ATPγS increased the release of IL-17. Overall these results clearly demonstrate for the first time that in normal human lung a stable ATP analogue can enhance LPS-induced pro-inflammatory cytokine release, and that these effects are greatly altered by a prior history of smoking. This provides strong support for the suggestion that nucleotides are involved in the pathogenesis of smoking-related diseases.
Highlights
There is increasing interest in the role of nucleotides in immune and inflammatory responses, and in particular their role in lung diseases [1]
The results presented here clearly show that smoking greatly increases the release of IL-1b and IFNc from human lungs in response to the non-hydrolysable ATP analogue, ATPcS, while reducing the release of IL-17
The basal levels of cytokine release were not significantly affected by smoking, and neither was the release in the presence of LPS, suggesting that smoking selectively affects the responses to nucleotides rather than acting to alter cytokine release non
Summary
There is increasing interest in the role of nucleotides in immune and inflammatory responses, and in particular their role in lung diseases [1]. In a mouse model of asthma, allergen challenge resulted in an increase in ATP concentrations in bronchoalveolar lavage fluid (BALF) and caused asthma-like symptoms which could be inhibited by administration of apyrase (which breaks down ATP) or by non-selective ATP antagonists such as suramin [3]. These findings were interpreted as indicating recruitment and activation of lung dendritic cells by ATP, resulting in induction of asthmalike responses. Reduced P2X7 function was associated with a lower incidence of asthma in children at high risk of the disease [9]
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