Lung epithelial-C/EBPβ contributes to LPS-induced inflammation and its suppression by formoterol.
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.
Department of Medicine, Respiratory Medicine Unit, Karolinska Institutet, Stockholm, Sweden. abraham.roos@ki.se
Abraham B
AB
Roos
Jenny L
JL
Barton
Anna
A
Miller-Larsson
Benita
B
Dahlberg
Tove
T
Berg
Lukas
L
Didon
Magnus
M
Nord
D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D018893:Bronchoalveolar Lavage; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*
D058666:Adrenergic beta-2 Receptor Agonists; D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D004983:Ethanolamines; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D000068759:Formoterol Fumarate