An essential regulatory role of downstream of kinase-1 in the ovalbumin-induced murine model of asthma |
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Authors: | Lee Chang-Min Jung In Duk Noh Kyung Tae Lee Jun Sik Park Jin Wook Heo Deok Rim Park Jun Ho Chang Jeong Hyun Choi Il-Whan Kim Jong-Suk Shin Yong Kyoo Park Sung-Joo Han Myung-Kwan Lee Chun Geun Cho Won-Kyung Park Yeong-Min |
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Affiliation: | Department of Microbiology and Immunology, Medical Research Institute, Pusan National University School of Medicine, Yang-san, South Korea. |
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Abstract: | The downstream of kinase (DOK)-1 is involved in the protein tyrosine kinase (PTK) pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK-1 significantly stimulated the activation and expression of STAT-4 and T-bet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT-6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases. |
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