Abstract
Cigarette smoke is the major risk factor for chronic obstructive pulmonary disease (COPD), a disease where inflammation and aging are intertwined. Sirtuin (Sirt)1, an anti-ageing factor, removes acetyl moieties and activates FoxO3, a transcriptional factor which controls cell cycle progression and inflammation. In the present study we investigated the relationship between these anti-aging factors and inflammatory processes (NF-κB, IL8 and CCL20 expression) in response to cigarette smoke. IL8 and CCL20 were selected as markers for innate and adaptive responses
16HBE cells and primary bronchial epithelial cells isolated from COPD patients and healthy controls,pre-treated with/without the Sirt1 inhibitor, Sirtinol, were stimulated with cigarette smoke extracts (CSE). The nuclear accumulation of Sirt1, FoxO3 and NF-κB, deacetylase activity of Sirt1 and IL8 and CCL20 expression (protein and mRNA) were evaluated.
The obtained results showed that (i) CSE decreases the activity and nuclear levels of Sirt1 in 16HBE cells; (ii) CSE reduces FoxO3 in 16HBE and in primary bronchial epithelial cells from healthy subjects; (iii) the expression of FoxO3 was more down-regulated in primary bronchial epithelial cells from COPD subjects than from healthy controls; (iv) CSE increased NF-κB and IL8 expression and decreased CCL20 expression. Pretreatment with Sirtinol reduces FoxO3 and increased NF-κB and IL8 expression but it had no effect on CCL20 expression.
These data suggest that cigarette smoke impairs the function of Sirt1 leading to deregulation of FoxO3 and NF-κB activity, modifying the cellular ageing and inflammatory processes with a prevalent activity of innate immune responses.
- Copyright ©ERS 2015