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

J.B.M. Jowett, Y. Okada, Peter Leedman, J.E. Curran, M.P. Johnson, Eric Moses, H.H.H. Goring, S. Mochizuki, J. Blangero, Leah Stone, Holly Allen, Chris Mitchell, Vance Matthews

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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. © 2013 Australasian Society for Immunology
Original languageEnglish
Pages (from-to)966-973
JournalImmunology and Cell Biology
Volume90
Issue number10
DOIs
Publication statusPublished - 25 Sep 2012

Fingerprint

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

Cite this

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

In: Immunology and Cell Biology, Vol. 90, No. 10, 25.09.2012, p. 966-973.

Research output: Contribution to journalArticle

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AU - Jowett, J.B.M.

AU - Okada, Y.

AU - Leedman, Peter

AU - Curran, J.E.

AU - Johnson, M.P.

AU - Moses, Eric

AU - Goring, H.H.H.

AU - Mochizuki, S.

AU - Blangero, J.

AU - Stone, Leah

AU - Allen, Holly

AU - Mitchell, Chris

AU - Matthews, Vance

PY - 2012/9/25

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N2 - 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. © 2013 Australasian Society for Immunology

AB - 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. © 2013 Australasian Society for Immunology

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