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Vol. 54, Issue 2, 264-272, August 1998
Department of Pharmacology and Program in Molecular Therapeutics
and Toxicology, The nuclear factor of activated T cells (NFAT) mediates a cyclosporin A
(CsA)- and FK506-suppressible transcriptional program in lymphocytes
after antigen-stimulated phospholipase C activation. Nonlymphoid cells
also express NFAT isoforms, raising the possibility that these
isoforms can be regulated by other extracellular stimuli. This
study sought to determine whether histamine can trigger NFAT-mediated transcription in human umbilical vein endothelial cells (HUVEC), using
a retrovirus-based luciferase reporter driven by a well characterized,
NFAT-specific enhancer. Luciferase levels are induced up to 60-fold
over basal levels after costimulation of HUVEC with Ca2+-mobilizing drugs and a phorbol ester, a response that
is 20-fold greater than that observed when HUVEC are stimulated with
either drug alone. These synergistic responses are inhibited in cells treated with CsA. CsA and FK506 also inhibit the luciferase response to
histamine, indicating that histamine can induce NFAT-mediated transcription in HUVEC. To identify candidate genes in HUVEC that might
be regulated by NFAT, the expression of several chemokine mRNAs was
measured after histamine treatment. Of the mRNAs tested, only those
encoding monocyte chemotactic protein-1 (~2-fold over basal) and
interleukin-8 (~6-fold over basal) are induced by histamine; both of
these responses are suppressed by CsA and FK506. The H1 histamine receptor antagonist chlorpheniramine, but not the
H2 receptor antagonist ranitidine, blocks the effects of
histamine in this preparation. These data provide the first evidence
for a physiological inducer of NFAT-mediated transcription in
endothelial cells and support the hypothesis that NFAT participates in
H1 histamine receptor-induced interleukin-8 gene
expression.
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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