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Characterisation of the tumour necrosis factor (TNF)-(alpha) response elements in the human ICAM-2 promoter

F McLaughlin1, V J Ludbrook, I Kola

  • 1Vascular Diseases Unit, GlaxoWellcome Medicines Research Centre, Stevenage, UK.

Journal of Cell Science
|November 27, 1999
PubMed

Insights

Tumor necrosis factor-alpha (TNF-α) down-regulates intercellular adhesion molecule-2 (ICAM-2) expression by affecting Ets transcription factors. This study identifies specific Ets binding sites in the ICAM-2 promoter involved in this cytokine-mediated gene regulation.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • Intercellular adhesion molecule-2 (ICAM-2) is crucial for leukocyte recruitment.
  • Pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) reduce ICAM-2 expression transcriptionally.

Purpose of the Study:

  • To identify the specific elements within the ICAM-2 promoter responsible for TNF-α-induced down-regulation.
  • To elucidate the molecular mechanisms underlying cytokine-mediated regulation of ICAM-2 expression.

Main Methods:

  • Site-directed mutagenesis of the ICAM-2 promoter.
  • Electrophoretic mobility shift assays (EMSA) in human umbilical vein endothelial cells (HUVEC).
  • Analysis of Ets transcription factor binding and protein levels, including Erg.

Main Results:

  • Two Ets binding sites (EBS) in the ICAM-2 promoter are critical for basal activity and TNF-α-mediated down-regulation.
  • TNF-α treatment reduced protein binding to the -135/-127EBS and decreased Erg protein levels in HUVEC.
  • Erg expression transactivated the ICAM-2 promoter, and both ICAM-2 and Erg showed similar TNF-α regulation in an ex vivo artery model.

Conclusions:

  • Constitutive endothelial genes ICAM-2 and Erg are regulated by the same cytokine-dependent pathway.
  • Ets transcription factors, particularly Erg, play a significant role in the TNF-α-mediated down-regulation of ICAM-2 expression.

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