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    The hydroxylase inhibitor DMOG attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B-1 cells


    Hams, Emily and Saunders, Sean P. and Cummins, Eoin P. and O'Connor, Aisling and Tambuwala, Murtaza T. and Gallagher, William M. and Byrne, Annette and Compos-Torres, Antonio and Moynagh, Paul N. and Jobin, Christian and Taylor, Cormac T and Fallon, Padraic G. (2011) The hydroxylase inhibitor DMOG attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B-1 cells. Shock, 36 (3). pp. 295-302. ISSN 1073-2322

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    Abstract

    Localized tissue hypoxia is a feature of infection and inflammation, resulting in the upregulation of the transcription factors HIF-1α and NF-κB via inhibition of oxygen sensing hydroxylase enzymes. Previous studies have demonstrated a beneficial role for the hydroxylase inhibitor dimethyloxallyl glycine (DMOG) in inflammatory conditions, including experimental colitis, by regulating the activity of HIF-1 and NF-κB. We have demonstrated in vivo that pre-treatment with DMOG attenuates systemic LPS-induced activation of the NF- κB pathway. Furthermore, mice treated with DMOG had significantly increased survival in LPS-induced shock. Conversely, in models of polymicrobial sepsis, DMOG exacerbates disease severity. DMOG treatment of mice promotes M2 polarization in macrophages within the peritoneal cavity, resulting in the downregulation of pro-inflammatory cytokines such as TNF α. In addition, in vivo DMOG treatment upregulates IL-10 expression, specifically in the peritoneal B-1 cell population. This study demonstrates cell type specific roles for hydroxylase inhibition in vivo and provides insight into the mechanism underlying the protection conveyed by DMOG in models of endotoxic shock.

    Item Type: Article
    Additional Information: The definitive published version of this article is available at Hams E, Saunders SP, Cummins EP, O'Connor A, Tambuwala MT, Gallagher WM, Byrne A, Campos-Torres A, Moynagh PN, Jobin C, Taylor CT, Fallon PG. (2011) 'The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells'. Shock, 36 :295-302. DOI: 10.1097/SHK.0b013e318225ad7e
    Keywords: LPS; hypoxia; mouse; NF-κB; tolerance;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 7189
    Identification Number: https://doi.org/10.1097/SHK.0b013e318225ad7e
    Depositing User: Professor Paul Moynagh
    Date Deposited: 15 Jul 2016 15:52
    Journal or Publication Title: Shock
    Publisher: Lippincott, Williams & Wilkins
    Refereed: Yes
    URI:

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