Sung Gil Ha1, Mythili Dileepan1, Xiao Na Ge1, Bit Na Kang1, Yana G Greenberg1, Amrita Rao1, Girija Muralidhar2, Lali Medina-Kauwe3, Michael A Thompson4, Christina M Pabelick5, Scott M O'Grady6, Savita P Rao1, P Sriramarao7. 1. Department of Veterinary & Biomedical Sciences, University of Minnesota, St Paul, Minn. 2. La Jolla Institute for Molecular Medicine, La Jolla, Calif. 3. Department of Biomedical Sciences, Cedars-Sinai Medical Center and Geffen School of Medicine, University of California-Los Angeles, Los Angeles, Calif. 4. Department of Anesthesiology, Mayo Clinic, Rochester, Minn. 5. Departments of Anesthesiology and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minn. 6. Departments of Animal Science and Integrative Biology and Physiology, University of Minnesota, St Paul, Minn. 7. Department of Veterinary & Biomedical Sciences, University of Minnesota, St Paul, Minn; Department of Medicine, University of Minnesota, Minneapolis, Minn. Electronic address: psrao@umn.edu.
Abstract
BACKGROUND: Altered epithelial physical and functional barrier properties along with TH1/TH2 immune dysregulation are features of allergic asthma. Regulation of junction proteins to improve barrier function of airway epithelial cells has the potential for alleviation of allergic airway inflammation. OBJECTIVE: We sought to determine the immunomodulatory effect of knob protein of the adenoviral capsid on allergic asthma and to investigate its mechanism of action on airway epithelial junction proteins and barrier function. METHODS: Airway inflammation, including junction protein expression, was evaluated in allergen-challenged mice with and without treatment with knob. Human bronchial epithelial cells were exposed to knob, and its effects on expression of junction proteins and barrier integrity were determined. RESULTS: Administration of knob to allergen-challenged mice suppressed airway inflammation (eosinophilia, airway hyperresponsiveness, and IL-5 levels) and prevented allergen-induced loss of airway epithelial occludin and E-cadherin expression. Additionally, knob decreased expression of TH2-promoting inflammatory mediators, specifically IL-33, by murine lung epithelial cells. At a cellular level, treatment of human bronchial epithelial cells with knob activated c-Jun N-terminal kinase, increased expression of occludin and E-cadherin, and enhanced epithelial barrier integrity. CONCLUSION: Increased expression of junction proteins mediated by knob leading to enhanced epithelial barrier function might mitigate the allergen-induced airway inflammatory response, including asthma.
BACKGROUND: Altered epithelial physical and functional barrier properties along with TH1/TH2 immune dysregulation are features of allergic asthma. Regulation of junction proteins to improve barrier function of airway epithelial cells has the potential for alleviation of allergic airway inflammation. OBJECTIVE: We sought to determine the immunomodulatory effect of knob protein of the adenoviral capsid on allergic asthma and to investigate its mechanism of action on airway epithelial junction proteins and barrier function. METHODS: Airway inflammation, including junction protein expression, was evaluated in allergen-challenged mice with and without treatment with knob. Human bronchial epithelial cells were exposed to knob, and its effects on expression of junction proteins and barrier integrity were determined. RESULTS: Administration of knob to allergen-challenged mice suppressed airway inflammation (eosinophilia, airway hyperresponsiveness, and IL-5 levels) and prevented allergen-induced loss of airway epithelial occludin and E-cadherin expression. Additionally, knob decreased expression of TH2-promoting inflammatory mediators, specifically IL-33, by murine lung epithelial cells. At a cellular level, treatment of human bronchial epithelial cells with knob activated c-Jun N-terminal kinase, increased expression of occludin and E-cadherin, and enhanced epithelial barrier integrity. CONCLUSION: Increased expression of junction proteins mediated by knob leading to enhanced epithelial barrier function might mitigate the allergen-induced airway inflammatory response, including asthma.
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