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.
Highlights
Asthma is Th2-mediated inflammatory disease characterized by airway hyperresponsiveness (AHR), and airway remodeling that results in bronchial eosinophil accumulation [1,2]
The expression of downstream of kinase (DOK)-1 was increased in the animals with OVA stimulation, and immunoreaction was remarkably negative for Downstream of tyrosine Kinase-1 (DOK-1) knockdown mice
These data demonstrate that DOK-1 expression is localized in the cytosol of airway epithelial cells, and its expression in the lung is efficiently modulated by lentiviral knockdown or transgenic approaches
Summary
Asthma is Th2-mediated inflammatory disease characterized by airway hyperresponsiveness (AHR), and airway remodeling that results in bronchial eosinophil accumulation [1,2]. Allergens trigger antigen-presenting cells to interact with naıve T cells [3,4] These events activate Th2 cells, resulting in the overproduction of various Th2 cytokines, such as interleukin (IL)-4, IL5 and IL-13, which are known to have a critical role in the differentiation in Th2 development [5,6,7]. Both clinical and experimental allergic inflammations lead to altered blood and lung profiles of Th1 and Th2 cytokines. IL-12 drives Th1 cell differentiation through activation of STAT 4 and T-box expressed in T cells (T-bet), Th1 transcription factor, which up-regulates IFN-c and down-regulates IL-4 and IL-5 production [12,17,18]
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