Sj. Lee et al., Transcriptional regulation of intercellular adhesion molecule-1 in astrocytes involves NF-kappa B and C/EBP isoforms, J NEUROIMM, 92(1-2), 1998, pp. 196-207
ICAM-1 is an inducible cell surface protein that is involved in cell extrav
asation into inflamed tissues as well as immune responses. ICAM-1 expressio
n is upregulated by proinflammatory cytokines such as TNF-alpha and IL-1 be
ta in numerous cell types including the astrocyte, which functions as an im
mune effector cell in the central nervous system (CNS). We investigated the
mechanism by which the ICAM-1 gene is transcriptionally regulated in astro
cytes in response to TNF-alpha and IL-1 beta. Human ICAM-1 promoter constru
cts linked to the reporter gene luciferase were transiently transfected int
o astrocytes, stimulated with TNF-alpha and IL-1 beta, and ICAM-1 promoter
activity examined. We determined that binding sites for both NF-kappa B (-1
86 bp region) and C/EBP (-198 bp region) are involved in TNF-alpha and LL-1
beta-mediated ICAM-1 upregulation. Electrophoretic mobility shift assays u
sing antibodies against NF-kappa B and C/EBP isoforms showed that p65 homod
imers and p65/p50 heterodimers bind to the NF-kappa B site, and C/EBP delta
homodimers and C/EBP beta/delta heterodimers bind to the C/EBP site. Trans
ient transfection assays demonstrated that overexpression of p65 could tran
sactivate the promoter activity of ICAM-1 reporter constructs. p50 overexpr
ession had no effect on the basal levels of ICAM-1 transcription, but inhib
ited, in a dose dependent manner, p65 mediated transcription. Overexpressio
n of C/EBP beta slightly inhibited basal levels of ICAM-1 promoter activity
, however, when C/EBP beta and p65 were cotransfected, C/EBP beta completel
y abolished the transactivating effects of p65. These results demonstrate t
hat cytokine-induced ICAM-1 expression in astrocytes is regulated by intera
ctions between NF-kappa B and C/EBP transcription factors. (C) 1998 Publish
ed by Elsevier Science B.V. All rights reserved.