PP-051 Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the JAK PKC-δ STAT1 signaling pathway in IFN-γ-stimulated murine dendritic cells

Abstract

Background: The downstream of kinase (DOK)-1, a 62 kDa adaptor protein, negatively regulates the protein tyrosine kinase (PTK) pathway in mast cells, but the role of DOK-1 in a murine model of asthma has not been defined. Methods: 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-1specific 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. Results: The transgenic introduction of DOK-1 significantly stimulates the activation and expression of STAT-4 and T-bet, while impressively inhibits the activation and expression of STAT-6 and GATA-3 in the 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. Conclusions: 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 that has therapeutic potential for asthma and other allergic diseases.