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.


OBJECTIVE
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-gamma, tumor necrosis factor-alpha).


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.
Chiappara
G
G
Istituto di Biomedicina e Immunologia Molecolare, Commessa di Immunopatologia e Farmacologia Sperimentale dell'Appartato Respiratorio, Consiglio Nazionale delle Ricerche, Palermo, Italy.
Chanez
P
P
Bruno
A
A
Pace
E
E
Pompeo
F
F
Bousquet
J
J
Bonsignore
G
G
Gjomarkaj
M
M
D000328:Adult; D001249:Asthma / Q000473:pathology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010766:Phosphorylation; D012720:Severity of Illness Index; D014018:Tissue Distribution
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids