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    ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-a

    Access Status
    Open access via publisher
    Authors
    Jowett, J.
    Okada, Y.
    Leedman, P.
    Curran, J.
    Johnson, M.
    Moses, Eric
    Goring, H.
    Mochizuki, S.
    Blangero, J.
    Stone, L.
    Allen, H.
    Mitchell, C.
    Matthews, V.
    Date
    2012
    Type
    Journal Article
    
    Metadata
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    Citation
    Jowett, J. and Okada, Y. and Leedman, P. and Curran, J. and Johnson, M. and Moses, E. and Goring, H. et al. 2012. ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-a. Immunology and Cell Biology. 90 (10): pp. 966-973.
    Source Title
    Immunology and Cell Biology
    DOI
    10.1038/icb.2012.44
    ISSN
    0818-9641
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/34989
    Collection
    • Curtin Research Publications
    Abstract

    Metalloproteinases are implicated in cleaving numerous proinflammatory mediators from the cell surface. Interestingly, the elevated levels of tumour necrosis factor-α (TNF-α) have been associated with the metabolic syndrome. We aimed to ascertain whether the human metalloproteinase ADAM28 correlates with parameters of the metabolic syndrome and whether ADAM28 is a novel sheddase of human TNF-α. To identify novel metalloproteinases associated with the metabolic syndrome, we conducted microarray studies on peripheral blood mononuclear cells from a well characterised human cohort. Human ADAM28 and TNF-α were overexpressed and ADAM28 expression or activity was reduced with small-interfering RNA (siRNA) or pharmacological inhibition. TNF-α levels were measured in cell supernatant by enzyme-linked immunosorbent assay. We also conducted ADAM28 inhibition studies in human THP-1 macrophages. Human ADAM28 expression levels were positively correlated with parameters of the metabolic syndrome. When human ADAM28 and TNF-α were overexpressed in HEK293 cells, both proteins co-localised, co-immunoprecipitated and promoted TNF-α shedding. The shedding was significantly reduced when ADAM28 activity was inhibited or ADAM28 expression was downregulated. In human THP-1 macrophages, endogenous ADAM28 and TNF-α were co-expressed and TNF-α shedding was significantly reduced when ADAM28 was inhibited by pharmacological inhibition or siRNA knockdown. Our data suggest a novel mechanistic role for the metalloproteinase ADAM28 in inflammation, obesity and type 2 diabetes.

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