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ADAM17 but not ADAM10 mediates tumor necrosis factor-alpha and L-selectin shedding from leukocyte membranes

T P Condon1, S Flournoy, G J Sawyer

  • 1Isis Pharmaceuticals, Carlsbad, CA 92008, USA. tcondon@isisph.com

Antisense & Nucleic Acid Drug Development
|May 4, 2001
PubMed

Insights

ADAM17, but not ADAM10, is the primary metalloprotease responsible for tumor necrosis factor-alpha (TNF-alpha) secretion and L-selectin shedding. Antisense oligonucleotides confirmed ADAM17

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Tumor necrosis factor-alpha (TNF-alpha) and L-selectin shedding are regulated by metalloproteases.
  • ADAM10 and ADAM17 are implicated in TNF-alpha release, while ADAM17 is linked to L-selectin shedding.
  • The precise roles of ADAM10 and ADAM17 in these processes require further elucidation.

Purpose of the Study:

  • To delineate the specific functions of ADAM10 and ADAM17 in TNF-alpha processing and L-selectin shedding.
  • To validate the efficacy of antisense oligonucleotides (ASOs) in targeting ADAM10 and ADAM17.

Main Methods:

  • Development and application of sequence-specific antisense oligonucleotides (ASOs) targeting ADAM10 and ADAM17.
  • Treatment of Jurkat and THP-1 cells with ASOs to assess mRNA reduction.
  • Quantification of TNF-alpha secretion and L-selectin shedding following ASO treatment.

Main Results:

  • ISIS 16337 effectively reduced ADAM17 mRNA levels in a dose-dependent manner in both cell lines.
  • ISIS 100750 specifically reduced ADAM10 mRNA levels in a dose-dependent manner.
  • ADAM17 ASO (ISIS 16337) significantly inhibited TNF-alpha secretion and L-selectin shedding, whereas ADAM10 ASO (ISIS 100750) showed no significant effect.

Conclusions:

  • ADAM17 is identified as a major metalloprotease responsible for both TNF-alpha processing and L-selectin shedding.
  • ADAM10's specific biological substrates in Jurkat and THP-1 cells remain to be identified.
  • ASOs targeting ADAM17 provide a potential strategy for modulating these shedding processes.

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