title: An essential regulatory role of downstream of kinase-1 in the ovalbumin-induced murine model of asthma.
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.
authors.affiliation: Department of Microbiology and Immunology, Medical Research Institute, Pusan National University School of Medicine, Yang-san, South Korea.
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Noh
authors.forename: Jun Sik
authors.initials: JS
authors.lastname: Lee
authors.forename: Jin Wook
authors.initials: JW
authors.lastname: Park
authors.forename: Deok Rim
authors.initials: DR
authors.lastname: Heo
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Park
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Chang
authors.forename: Il-Whan
authors.initials: IW
authors.lastname: Choi
authors.forename: Jong-Suk
authors.initials: JS
authors.lastname: Kim
authors.forename: Yong Kyoo
authors.initials: YK
authors.lastname: Shin
authors.forename: Sung-Joo
authors.initials: SJ
authors.lastname: Park
authors.forename: Myung-Kwan
authors.initials: MK
authors.lastname: Han
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Cho
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D010047:Ovalbumin / Q000633:toxicity*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; D050990:GATA3 Transcription Factor; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D010047:Ovalbumin