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 journalArticle

11 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Metalloproteases
Tumor Necrosis Factor-alpha
Small Interfering RNA
Macrophages
Pharmacology
HEK293 Cells
Type 2 Diabetes Mellitus
Blood Cells
Down-Regulation
Obesity
Enzyme-Linked Immunosorbent Assay
human TNF protein
Inflammation
Proteins

Keywords

  • Cytokines
  • Insulin resistance
  • Metabolism
  • Metalloproteinase

ASJC Scopus subject areas

  • Immunology
  • Cell Biology

Cite this

Jowett, J. B. M., Okada, Y., Leedman, P. J., Curran, J. E., Johnson, M. P., Moses, E. K., ... Matthews, V. B. (2012). ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-α. Immunology and Cell Biology, 90(10), 966-973. https://doi.org/10.1038/icb.2012.44

ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-α. / Jowett, Jeremy B M; Okada, Yasunori; Leedman, Peter J.; Curran, Joanne E.; Johnson, Matthew P.; Moses, Eric K.; Goring, Harald H H; Mochizuki, Satsuki; Blangero, John; Stone, Leah; Allen, Holly; Mitchell, Chris; Matthews, Vance B.

In: Immunology and Cell Biology, Vol. 90, No. 10, 11.2012, p. 966-973.

Research output: Contribution to journalArticle

Jowett, JBM, Okada, Y, Leedman, PJ, Curran, JE, Johnson, MP, Moses, EK, Goring, HHH, Mochizuki, S, Blangero, J, Stone, L, Allen, H, Mitchell, C & Matthews, VB 2012, 'ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-α', Immunology and Cell Biology, vol. 90, no. 10, pp. 966-973. https://doi.org/10.1038/icb.2012.44
Jowett, Jeremy B M ; Okada, Yasunori ; Leedman, Peter J. ; Curran, Joanne E. ; Johnson, Matthew P. ; Moses, Eric K. ; Goring, Harald H H ; Mochizuki, Satsuki ; Blangero, John ; Stone, Leah ; Allen, Holly ; Mitchell, Chris ; Matthews, Vance B. / ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-α. In: Immunology and Cell Biology. 2012 ; Vol. 90, No. 10. pp. 966-973.
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