Cigarette smoke inhibits bacteria-induced FABP5 expression by preventing c-Jun binding to FABP5 promoter

Abstract

Cigarette smoking is the primary cause of chronic obstructive pulmonary disease (COPD). Repeated and sustained bacterial infections are clearly linked to disease pathogenesis and exacerbations. The epithelium constitutes the first line of host defense against infection but the mechanisms of impaired bacterial clearance within airway epithelial cells of COPD patients have yet to be understood. We have recently identified Fatty Acid Binding Protein 5 (FABP5) as an important player during respiratory infections. Our previous data indicate that cigarette smoke down regulates FABP5 expression and that overexpression of FABP5 in primary airway epithelial cells protects against bacterial infection. However, the regulation of FABP5 by cigarette smoke or bacterial infection remains unknown. We found that c-Jun inhibition prevents bacteria-induced FABP5 expression and that there are four putative c-Jun binding sites within the FABP5 promoter sequence. To show that c-Jun binds FABP5 promoter and regulates its transcription, we performed a chromatin immunoprecipitation (ChIP) assay. Protein/DNA extract of airway epithelial cells treated with cigarette smoke and/or LPS were immunoprecipitated with c-Jun specific antibodies. Using PCR primers flanking the c-Jun binding sites, we determined that c-Jun binds FABP5 promoter when stimulated with LPS but the presence of cigarette smoke greatly reduced c-Jun9s ability to bind to the FABP5 promoter. These data demonstrate that cigarette smoke interferes with FABP5 expression in response to bacterial infection. Functional activation of FABP5 may be a new therapeutic strategy when treating COPD patients suffering from exacerbations.