Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation

• DOI: 10.1172/jci.insight.87168
• Publication Date: 2016-07-20T15:00:45Z
• Authors: Kong Chen; Brian T. Campfield; Sally E. Wenzel; Jeremy P. McAleer; James L. Kreindler; Geoffrey Kurland; Radha Gopal; Ting Wang; Wei Chen; Taylor Eddens; Kathleen M. Quinn; Mike M. Myerburg; William T. Horne; Jose M. Lora; Brian K. Albrecht; Joseph M. Pilewski; Jay. K. Kolls
• Keywords: efferocytosis

Significant morbidity in cystic fibrosis (CF) results from chronic lung inflammation, most commonly due to Pseudomonas aeruginosa infection. Recent data suggest that IL-17 contributes pathological inflammation the setting of abnormal mucosal immunity, and type 17 immunity–driven inflammatory responses may represent a target block aberrant CF. Indeed, transcriptomic analysis airway epithelium CF patients undergoing clinical bronchoscopy revealed upregulation downstream signature genes, implicating substantial contribution IL-17–mediated immunity lungs. Bromodomain extraterminal domain (BET) chromatin modulators can regulate T cell responses, specifically Th17-mediated by mechanisms include bromodomain-dependent inhibition acetylated histones at IL17 locus. Here, we show that, vitro, BET potently suppressed Th17 explanted tissue inhibited IL-17–driven chemokine production human bronchial epithelial cells. In an acute P. infection murine model, decreased without exacerbating infection, suggesting be potential therapeutic with