Lung epithelial-C/EBPβ contributes to LPS-induced inflammation and its suppression by formoterol.

Abstract

The inflammatory processes associated with pulmonary disorders remains incompletely understood. CCAAT/enhancer-binding protein (C/EBP)β is implicated in inflammatory lung disorders as well as in β(2)-adrenoceptor signaling. We hypothesized that C/EBPβ in the lung epithelium contributes to lipopolysaccharide (LPS)-induced airway neutrophilia and expression of neutrophil chemoattractant chemokine (C-X-C) motif ligand (CXCL)1, as well as the suppressive effects of long-acting β(2)-agonists (LABAs) and glucocorticoids (GCs). To investigate this, mice with a lung epithelial-specific deletion of C/EBPβ (Cebpb(ΔLE)) and control littermates (Cebpb(fl/fl)) were pre-treated with a LABA, formoterol and/or a GC, budesonide, and challenged with LPS. Inflammatory cell recruitment in bronchoalveolar lavage (BAL) fluid and pulmonary expression of inflammatory mediators were investigated. In addition, the ability of formoterol to increase C/EBP transactivation was assessed in vitro. LPS-challenged Cebpb(ΔLE) mice exhibited fewer BAL neutrophils and lower pulmonary expression of CXCL1 versus Cebpb(fl/fl) mice. Suppression of LPS-induced neutrophilia by formoterol was impaired in Cebpb(ΔLE) mice and Cxcl1 expression was increased. However, suppression of the neutrophilia by budesonide with/without formoterol was preserved. Further studies indicated that C/EBP transactivation was increased by the cAMP elevating agent forskolin and formoterol in a β(2)-adrenoceptor dependent manner. Thus, C/EBPβ in the lung epithelium contributes to LPS-induced CXCL1 expression and airway neutrophilia as well as to the suppressive effects of formoterol. Reduced C/EBPβ activity, observed in smokers with chronic obstructive pulmonary disease, may impair the responsiveness to LABAs when used without GCs.

• Authors: Abraham B Roos, Jenny L Barton, Anna Miller-Larsson, Benita Dahlberg, Tove Berg, Lukas Didon, Magnus Nord
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 423 Issue 1 Pg. 134-9 (Jun 22 2012) ISSN: 1090-2104 [Electronic] United States
• PMID: 22634316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Adrenergic beta-2 Receptor Agonists
• CCAAT-Enhancer-Binding Protein-beta
• Cebpb protein, mouse
• Chemokine CXCL1
• Cxcl1 protein, mouse
• Ethanolamines
• Glucocorticoids
• Lipopolysaccharides
• Formoterol Fumarate

Topics

• Adrenergic beta-2 Receptor Agonists (pharmacology)
• Animals
• Bronchoalveolar Lavage
• CCAAT-Enhancer-Binding Protein-beta (genetics, metabolism)
• Chemokine CXCL1 (antagonists & inhibitors, biosynthesis)
• Ethanolamines (pharmacology)
• Formoterol Fumarate
• Glucocorticoids (pharmacology)
• Humans
• Lipopolysaccharides (pharmacology)
• Lung (metabolism)
• Mice
• Mice, Mutant Strains
• Neutrophils (drug effects, metabolism, pathology)
• Pneumonia (metabolism)
• Respiratory Mucosa (drug effects, metabolism)