Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation
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
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
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Research Article Inflammation Therapeutics

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

Abstract

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

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

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Figure 2

CPI-203 potently suppresses Th17 cytokine production by T cells from CF lungs.

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CPI-203 potently suppresses Th17 cytokine production by T cells from CF ...
(A) Mononuclear cells from CF lung explants were stimulated with human T cell expander beads (anti-CD3/anti-CD28) for 4 days in the presence of indicated concentrations of CPI-203. Tissue culture supernatants were harvested and IL-17A and IL-22 were measured by ELISA. Data are represented by normalization against conditions without the compound for each donor. Donor genotypes are summarized in Supplemental Table 3. (B) After the supernatants were harvested, cells were harvested in TriZol for RNA extraction, and gene expression was determined by real-time RT-PCR. Data are represented by normalization against conditions without the compound for each donor. (C) Mononuclear cells from CF lung explants were restimulated with PMA/ionomycin in the presence of Golgi-plug for 4 hours before harvesting for intracellular cytokine staining analysis. Representative FACS plots of mLN cells are shown. *P < 0.05, ***P < 0.0005 by ANOVA.