Variable p‐CREB expression depicts different asthma phenotypes

Background:  Chromatin modification may play a role in inflammatory gene regulation in asthma. Cyclic adenosine mono‐phosphate response element‐binding protein (CREB), with the specific co‐activator, the CREB‐binding protein (CBP), contributes to the acetylation of chromatin and to the transcription of pro‐inflammatory genes.Objectives:  To evaluate the expression of CBP and of phospho‐CREB (p‐CREB) in bronchial biopsies and in peripheral blood mononuclear cells (PBMC) of controls (C), untreated (UA), inhaled steroid treated (ICS) and steroid‐dependent asthmatic (SDA) patients.Methods:  We used immunohistochemistry in bronchial biopsies and western blot analysis and immunocytochemistry in PBMC.Results:  Cyclic adenosine mono‐phosphate response element‐binding protein expression, in the epithelium was similar in all groups, while p‐CREB expression was increased in UA and in SDA in comparison with ICS and C subjects (C vs UA P = 0.002, C vs SDA P = 0.007), (ICS vs SDA P = 0.005), (ICS vs UA P = 0.001). Interestingly, also in the submucosa, p‐CREB was increased in UA and SDA in comparison with ICS and C subjects (C vs UA P = 0.0004) (C vs SDA P < 0.0001) (ICS vs UA P = 0.002) (ICS vs SDA P < 0.0001) and positively correlated with leukocyte infiltration within the bronchi (CD45RB+ cells). Similar results were obtained with PBMC isolated from the same patient groups. Incubation of PBMC in vitro, with fluticasone propionate, decreased the p‐CREB expression induced by cytokine activation (interferon‐γ, tumor necrosis factor‐α).Conclusions:  This study demonstrates that the expression of p‐CREB is related, in asthma, to the persistent inflammation according to the disease severity. p‐CREB expression can be modulated by glucocorticoids in responsive patients.