Variable p-CREB expression depicts different asthma phenotypes

Allergy. 2007 Jul;62(7):787-94. doi: 10.1111/j.1398-9995.2007.01417.x.

Abstract

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asthma / pathology*
  • Cyclic AMP Response Element-Binding Protein / analysis*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Female
  • Gene Expression Regulation / drug effects
  • Glucocorticoids / pharmacology
  • Humans
  • Immunohistochemistry
  • Inflammation / diagnosis*
  • Male
  • Middle Aged
  • Phenotype
  • Phosphorylation
  • Severity of Illness Index*
  • Tissue Distribution

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Glucocorticoids