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Transcriptional regulation of the intercellular adhesion molecule‐1 gene by proinflammatory cytokines in human astrocytes
Author(s) -
Lee Sung Joong,
Park Joo Young,
Hou Jinzhao,
Benveniste Etty N.
Publication year - 1999
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/(sici)1098-1136(19990101)25:1<21::aid-glia3>3.0.co;2-r
Subject(s) - proinflammatory cytokine , biology , tumor necrosis factor alpha , microbiology and biotechnology , downregulation and upregulation , astrocyte , intercellular adhesion molecule 1 , cell adhesion molecule , reporter gene , gene expression , immunology , inflammation , central nervous system , biochemistry , neuroscience , gene
Intercellular adhesion molecule‐1 (ICAM‐1) expression is upregulated by cytokines such as tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), and interferon‐γ (IFN‐γ) 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‐α and IL‐1β enhanced ICAM‐1 expression at both the mRNA and protein levels, while IFN‐γ had a modest enhancing effect. However, a synergistic response was noted when IFN‐γ was added with either TNF‐α or IL‐1β. Using human ICAM‐1 deletion constructs and linker scanning mutants, we determined that the NF‐κB element (‐186 bp region) is critical for both TNF‐α‐ and IL‐1β‐mediated ICAM‐1 expression, while the IFN‐γ activation sequence (GAS) element at ‐75 bp region is important for IFN‐γ stimulation. The synergistic effect between TNF‐α and IFN‐γ is dependent on both NF‐κB and GAS elements. Upon TNF‐α and IL‐1β stimulation, p65 homodimers and p65/p50 heterodimers bind to the NF‐κB site, and STAT‐1α homodimers bind to the GAS element upon IFN‐γ 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‐α or IL‐1β stimulation, and that IFN‐γ enhancement of ICAM‐1 involves activation of STAT‐1α homodimers. GLIA 25:21–32, 1999. © 1999 Wiley‐Liss, Inc.