Hyun Seung Lee1, Heung-Woo Park2, Woo-Jung Song2, Eun Young Jeon1, Boram Bang1, Eun-Jin Shim1, Hyung-Geun Moon3, Yoon-Keun Kim3, Hye-Ryun Kang2, Kyung-Up Min2, Sang-Heon Cho4. 1. Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea. 2. Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. 3. Department of Life Science and Division of Molecular and Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. 4. Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: shcho@snu.ac.kr.
Abstract
BACKGROUND: TNF-α has been postulated to be a critical mediator contributing to airway inflammation. The purpose of this study was to evaluate the role of TNF-α in the induction of Th17 and Th2 cells related to asthma pathogenesis. OBJECTIVE: To evaluate detailed mechanisms for the modulation of IL-23 by TNF-α in sensitization period. METHODS: During sensitization period, 10μg of rat anti-mouse TNF-α mAb was intravenously administrated one hour before the application of OVA and 0.1μg of LPS. To see the relation between TNF-α and associated effectors cytokine, we replenished TNF-α KO mice with IL-23 during sensitization period. To assess cellular resources, CD11c+ cells isolated from lung tissue after sensitization were treated with anti-TNF-α Ab. RESULTS: Treatment of anti-TNF-α mAb during sensitization period significantly reduced airway eosinophilia, serum OVA-specific IgE levels and methacholine AHR compared to isotype Ab. Anti-TNF-α mAb treated mice showed significant reduction in the levels of IL-23 after sensitization in bronchoalveolar lavage fluid (BALF) as well as IL-17A, IL-4 levels in BALF after challenge compared with isotype Ab treated mice. Supplementation of IL-23 in TNF-α KO mice resulted in complete restoration of eosinophilic airway inflammation, AHR, and IL-17A and IL-4 expression in CD4+ T cells. Anti-TNF-α mAb treatment after sensitization significantly diminished the population of IL-23p19-secreting CD11c+ cells in lung. CONCLUSION: TNF-α plays an important role in the development of airway inflammation by enhancing IL-23/Th17 and Th2 immune responses.
BACKGROUND: TNF-α has been postulated to be a critical mediator contributing to airway inflammation. The purpose of this study was to evaluate the role of TNF-α in the induction of Th17 and Th2 cells related to asthma pathogenesis. OBJECTIVE: To evaluate detailed mechanisms for the modulation of IL-23 by TNF-α in sensitization period. METHODS: During sensitization period, 10μg of rat anti-mouse TNF-α mAb was intravenously administrated one hour before the application of OVA and 0.1μg of LPS. To see the relation between TNF-α and associated effectors cytokine, we replenished TNF-α KO mice with IL-23 during sensitization period. To assess cellular resources, CD11c+ cells isolated from lung tissue after sensitization were treated with anti-TNF-α Ab. RESULTS: Treatment of anti-TNF-α mAb during sensitization period significantly reduced airway eosinophilia, serum OVA-specific IgE levels and methacholineAHR compared to isotype Ab. Anti-TNF-α mAb treated mice showed significant reduction in the levels of IL-23 after sensitization in bronchoalveolar lavage fluid (BALF) as well as IL-17A, IL-4 levels in BALF after challenge compared with isotype Ab treated mice. Supplementation of IL-23 in TNF-α KO mice resulted in complete restoration of eosinophilic airway inflammation, AHR, and IL-17A and IL-4 expression in CD4+ T cells. Anti-TNF-α mAb treatment after sensitization significantly diminished the population of IL-23p19-secreting CD11c+ cells in lung. CONCLUSION: TNF-α plays an important role in the development of airway inflammation by enhancing IL-23/Th17 and Th2 immune responses.
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