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 β2-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 β2-agonists (LABAs) and glucocorticoids (GCs).To investigate this, mice with a lung epithelial-specific deletion of C/EBPβ (CebpbΔLE) and control littermates (Cebpbfl/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 CebpbΔLE mice exhibited fewer BAL neutrophils and lower pulmonary expression of CXCL1 versus Cebpbfl/fl mice. Suppression of LPS-induced neutrophilia by formoterol was impaired in CebpbΔLE 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 β2-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.

► We examined C/EBPβ in pulmonary inflammation and suppression by formoterol.
► C/EBPβ contributes to LPS-induced pulmonary neutrophilia and CXCL1 expression.
► C/EBPβ plays a role in suppression of Cxcl1 and Il6 by formoterol.
► We propose that C/EBPβ contributes to both pro- and anti-inflammatory effects.