title: Dok adaptors play anti-inflammatory roles in pulmonary homeostasis.
abstract: Asthma is a chronic inflammatory disease of the lung with airflow obstruction and bronchospasm, characterized by pulmonary eosinophilia, airway remodeling, increased airway hyperresponsiveness to environmental stimuli, and excessive Th2-type cytokine production. Recent studies indicate that crosstalk between the innate and adaptive immune systems is crucial for this disease. We and others have showed that the Dok (downstream of tyrosine kinases) family adaptors, Dok-1, Dok-2, and Dok-3, play essential roles in negative regulation of a wide variety of signaling pathways in both innate and adaptive immunities. Here, histopathology and bronchoalveolar lavage fluid (BALF) cellularity showed spontaneous pulmonary inflammation in Dok-1-/- Dok-2-/- Dok-3-/- (TKO) mice, but not in Dok-1-/- Dok-2-/- or Dok-3-/- mice, with hallmarks of asthma, including eosinophilia, goblet cell hyperplasia, and subepithelial fibrosis. Consistently, TKO mice, but not the other mutants, showed increased airway hyperresponsiveness to methacholine inhalation. In addition, Th2-type cytokine concentrations in BALF were increased in TKO mice. These findings provide strong evidence that Dok-1, Dok-2, and Dok-3 cooperatively play critical anti-inflammatory roles in lung homeostasis.
authors.affiliation: Division of Genetics, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Mashima
authors.forename: Sumimasa
authors.initials: S
authors.lastname: Arimura
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kajikawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oda
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamanashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005355:Fibrosis / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D006965:Hyperplasia / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008168:Lung / Q000473:pathology*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology; D011014:Pneumonia / Q000235:genetics / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D020545:Respiratory Mucosa / Q000473:pathology; D018418:Th2 Cells / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016085:Bronchoconstrictor Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; C406768:Dok3 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D016210:Methacholine Chloride