| OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis. | |
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MedLine Citation:
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PMID: 20844189 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The initial phase of sepsis is characterized by massive inflammatory cytokine production that contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity. Recent studies described their presence on neutrophils and monocytes, suggesting a potential role in the regulation of cytokine production in innate immunity. The purpose of this study was to determine the role for OX40-OX40 ligand (OX40L) interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on monocytes and neutrophils, with mortality and intensive care unit stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was indicated by improved survival, decreased cytokine production, and a decrease in remote organ damage in OX40L(-/-) mice. The finding of similar results with an OX40L Ab suggests a potential therapeutic role for OX40L blockade in sepsis. The inability of anti-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensable cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of anti-OX40L Ab in RAG1(-/-) mice further confirms a T cell-independent role for OX40L stimulation in sepsis. In conclusion, our data provide an in vivo role for the OX40/OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder. |
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Authors:
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Matthew Karulf; Ann Kelly; Andrew D Weinberg; Jeffrey A Gold |
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Publication Detail:
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Type: Journal Article Date: 2010-09-15 |
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 Oct |
Date Detail:
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Created Date: 2010-10-06 Completed Date: 2010-11-04 Revised Date: 2011-03-10 |
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: 4856-62 Citation Subset: AIM; IM |
Affiliation:
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Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Providence Portland Medical Center, Portland, OR 97239, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Animals Cell Separation Female Flow Cytometry Humans Immunity, Innate* Immunoassay Inflammation / immunology, metabolism Male Membrane Glycoproteins / immunology*, metabolism Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Monocytes / immunology, metabolism OX40 Ligand / immunology*, metabolism Receptors, OX40 / immunology, metabolism Sepsis / immunology*, metabolism, mortality Tumor Necrosis Factors / immunology*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA102577-08/CA/NCI NIH HHS; R01 CA122701-05/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Membrane Glycoproteins; 0/OX40 Ligand; 0/Receptors, OX40; 0/TNFSF4 protein, human; 0/Tnfsf4 protein, mouse; 0/Tumor Necrosis Factors |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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