Interleukin-6 Contributes to Inflammation and Remodeling in a Model of Adenosine Mediated Lung Injury

Abstract

BackgroundChronic lung diseases are the third leading cause of death in the United States due in part to an incomplete understanding of pathways that govern the progressive tissue remodeling that occurs in these disorders. Adenosine is elevated in the lungs of animal models and humans with chronic lung disease where it promotes air-space destruction and fibrosis. Adenosine signaling increases the production of the pro-fibrotic cytokine interleukin-6 (IL-6). Based on these observations, we hypothesized that IL-6 signaling contributes to tissue destruction and remodeling in a model of chronic lung disease where adenosine levels are elevated.Methodology/Principal FindingsWe tested this hypothesis by neutralizing or genetically removing IL-6 in adenosine deaminase (ADA)-deficient mice that develop adenosine dependent pulmonary inflammation and remodeling. Results demonstrated that both pharmacologic blockade and genetic removal of IL-6 attenuated pulmonary inflammation, remodeling and fibrosis in this model. The pursuit of mechanisms involved revealed adenosine and IL-6 dependent activation of STAT-3 in airway epithelial cells.Conclusions/SignificanceThese findings demonstrate that adenosine enhances IL-6 signaling pathways to promote aspects of chronic lung disease. This suggests that blocking IL-6 signaling during chronic stages of disease may provide benefit in halting remodeling processes such as fibrosis and air-space destruction.

B lymphocytes regulate airway granulocytic inflammation and cytokine production in a murine model of fungal allergic asthma

“…12,[58][59][60] Similarly, the neutralization of IL-6 has been associated with decreased inflammation in allergic mice, and this phenomenon occurs in conjunction with IL-17A, indicating that IL-6 regulates IL-17A production in models of lung injury. 41 Consistent with these observations, we also observed an increased IL-17 and IL-6 response in the absence of B lymphocytes in J H 2/2 mice. Thus, we hypothesized that, in the absence of B cells, the induction of IL-6/IL-17A axis results in increased granulocytic inflammation in the airways of J H 2/2 mice compared with the BALB/c mice, in which IL-6/IL-17A production was significantly attenuated.…”

“…might be involved in mediating granulocytic influx in the absence of B lymphocytes. IL-6 and IL-17A have been associated with granulocyte recruitment in other allergy models, [37][38][39][40][41] so we assessed the levels of these cytokines in the fungal model to determine whether they could be responsible for the increased granulocytic inflammation seen in the absence of B cells. After the third conidia challenge, the levels of IL-6 ( Figure 9a) and IL-17A ( Figure 9b) were significantly higher in the BAL fluid of J H 2/2 mice than in the BAL fluid of BALB/c mice, consistent with increased numbers of neutrophils and eosinophils in the BAL compartment of the J H 2/2 mice at D3 (IH3).…”

“…Recent studies have revealed that Th17 cells, a new T-helper cell lineage that produces IL-17 and related cytokines might have important roles in the development of pulmonary inflammation and AHR. IL-6 also promotes inflammation and pulmonary fibrosis, 41,56 suggesting that the 'Th2 theory' is probably inadequate to explain the diverse forms of asthma in humans and the various inflammatory responses observed in animal models of allergic asthma. 12,57,58 In recent years, a number of research groups have demonstrated a more direct role for IL-17 in exacerbating eosinophilia and neutrophilia.…”

Increased IgA production by B-cells in COPDvialung epithelial interleukin-6 and TACI pathways

“…Interestingly, the blockade of IL-6 significantly suppressed IgA induction by COPD epithelial cells. It was reported that deletion of IL-6 attenuated lung inflammation and fibrosis in a murine model of adenosine-mediated injury [38], and that a genetic polymorphism (IL6 −174G/C) was associated with susceptibility to COPD [39]. Moreover, it was ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ • ■ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ …”

Overexpression of CD39 in Mouse Airways Promotes Bacteria-Induced Inflammation

“…The increase of lymphocyte influx in transgenic lungs can therefore not be explained by elevated adenosine levels and adenosine receptor activation and would rather depend on P2 receptors. Because adenosine promotes the production of IL-6 by many cell types through engagement of the A 2B R, contributing to inflammation and fibrosis (47), it is possible that the increase of IL-6 levels in BALF of LPS-treated transgenic mice would be mediated at least partially by adenosine. Detailed assessment of differential contribution of adenosine receptor subtypes to our transgenic phenotype would require the availability of selective antagonists or their genetic ablation in an hCD39-overexpressing background.…”