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

Jeremy B.M. Jowett, Yasunori Okada, Peter J. Leedman, Joanne E. Curran, Matthew P. Johnson, Eric K. Moses, Harald H.H. Goring, Satsuki Mochizuki, John Blangero, Leah Stone, Holly Allen, Chris Mitchell, Vance B. Matthews

    Research output: Contribution to journalArticlepeer-review

    12 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)966-973
    Number of pages8
    JournalImmunology and Cell Biology
    Volume90
    Issue number10
    DOIs
    StatePublished - Nov 2012

    Keywords

    • Cytokines
    • Insulin resistance
    • Metabolism
    • Metalloproteinase

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology
    • Cell Biology

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