Transcriptional regulation of the intercellular adhesion molecule-1 gene by proinflammatory cytokines in human astrocytes.

Academic Article

Abstract

  • Intercellular adhesion molecule-1 (ICAM-1) expression is upregulated by cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interferon-gamma (IFN-gamma) in numerous cell types including the astrocyte, which functions as an immunoregulatory cell within the central nervous system. We investigated the mechanism by which ICAM-1 is transcriptionally regulated by proinflammatory cytokines in human fetal astrocytes. TNF-alpha and IL-1beta enhanced ICAM-1 expression at both the mRNA and protein levels, while IFN-gamma had a modest enhancing effect. However, a synergistic response was noted when IFN-gamma was added with either TNF-alpha or IL-1beta. Using human ICAM-1 deletion constructs and linker scanning mutants, we determined that the NF-kappaB element (-186 bp region) is critical for both TNF-alpha- and IL-1beta-mediated ICAM-1 expression, while the IFN-gamma activation sequence (GAS) element at -75 bp region is important for IFN-gamma stimulation. The synergistic effect between TNF-alpha and IFN-gamma is dependent on both NF-kappaB and GAS elements. Upon TNF-alpha and IL-1beta stimulation, p65 homodimers and p65/p50 heterodimers bind to the NF-kappaB site, and STAT-1alpha homodimers bind to the GAS element upon IFN-gamma stimulation. Transient transfection assays demonstrated that overexpression of the p65 protein transactivated the promoter activity of an ICAM-1 reporter construct, while p50 overexpression inhibited, in a dose-dependent manner, p65-mediated ICAM-1 expression. These data collectively suggest that in human astrocytes, the p65 homodimer is responsible for ICAM-1 upregulation upon TNF-alpha or IL-1beta stimulation, and that IFN-gamma enhancement of ICAM-1 involves activation of STAT-1alpha homodimers.
  • Published In

  • Glia  Journal
  • Keywords

  • Astrocytes, Cytokines, Flow Cytometry, Galactosidases, Humans, Indicators and Reagents, Intercellular Adhesion Molecule-1, Interferon-gamma, Interleukin-1, Luciferases, Microscopy, Fluorescence, NF-kappa B, RNA, Ribonucleases, Transfection, Tumor Necrosis Factor-alpha, Up-Regulation
  • Author List

  • Lee SJ; Park JY; Hou J; Benveniste EN
  • Start Page

  • 21
  • End Page

  • 32
  • Volume

  • 25
  • Issue

  • 1