| Notch ligand delta-like 4 regulates development and pathogenesis of allergic airway responses by modulating IL-2 production and Th2 immunity. | |
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MedLine Citation:
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PMID: 20944009 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Activation of the canonical Notch pathways has been implicated in Th cell differentiation, but the role of specific Notch ligands in Th2-mediated allergic airway responses has not been completely elucidated. In this study, we show that delta-like ligand 4 (Dll4) was upregulated on dendritic cells in response to cockroach allergen. Blocking Dll4 in vivo during either the primary or secondary response enhanced allergen-induced pathogenic consequences including airway hyperresponsiveness and mucus production via increased Th2 cytokines. In vitro assays demonstrated that Dll4 regulates IL-2 in T cells from established Th2 responses as well as during primary stimulation. Notably, Dll4 blockade during the primary, but not the secondary, response increased IL-2 levels in lung and lymph node of allergic mice. The in vivo neutralization of Dll4 was associated with increased expansion and decreased apoptosis during the primary allergen sensitization. Moreover, Dll4-mediated Notch activation of T cells during primary stimulation in vitro increased apoptosis during the contraction/resting phase of the response, which could be rescued by exogenous IL-2. Consistent with the role for Dll4-mediated IL-2 regulation in overall T cell function, the frequency of IL-4-producing cells was also significantly altered by Dll4 both in vivo and in vitro. These data demonstrate a regulatory role of Dll4 both in initial Th2 differentiation and in Th2 cytokine production in established allergic responses. |
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Authors:
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Sihyug Jang; Matthew Schaller; Aaron A Berlin; Nicholas W Lukacs |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-10-13 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 185 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-04 Completed Date: 2010-12-02 Revised Date: 2011-11-21 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 5835-44 Citation Subset: AIM; IM |
Affiliation:
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Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Differentiation / immunology Cell Separation Dendritic Cells / immunology, metabolism Flow Cytometry Interleukin-2 / biosynthesis*, immunology Intracellular Signaling Peptides and Proteins / immunology*, metabolism Lymphocyte Activation / immunology Membrane Proteins / immunology*, metabolism Mice Mice, Inbred BALB C Respiratory Hypersensitivity / immunology*, metabolism Reverse Transcriptase Polymerase Chain Reaction Th2 Cells / cytology, immunology*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AI036302/AI/NIAID NIH HHS; AI073876/AI/NIAID NIH HHS; R01 AI036302-14/AI/NIAID NIH HHS; R01 AI073876-04/AI/NIAID NIH HHS; R01 AI073876-05/AI/NIAID NIH HHS; T32 HL007517/HL/NHLBI NIH HHS; T32 HL007517-26A2/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DLL4 protein, mouse; 0/Interleukin-2; 0/Intracellular Signaling Peptides and Proteins; 0/Membrane Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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