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.