HISTAMINE INDUCES NUCLEAR FACTOR OF ACTIVATED T-CELL-MEDIATED TRANSCRIPTION AND CYCLOSPORINE-A-SENSITIVE INTERLEUKIN-8 MESSENGER-RNA EXPRESSION IN HUMAN UMBILICAL VEIN ENDOTHELIAL-CELLS

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 cell s also express NFAT isoforms, raising the possibility that these isofo rms can be regulated by other extracellular stimuli. This study sought to determine whether histamine can trigger NFAT-mediated transcriptio n in human umbilical vein endothelial cells (HUVEC), using a retroviru s-based luciferase reporter driven by a well characterized, NFAT-speci fic enhancer. Luciferase levels are induced up to 60-fold over basal l evels after costimulation of HUVEC with Ca2+-mobilizing drugs and a ph orbol ester, a response that is 20-fold greater than that observed whe n HUVEC are stimulated with either drug alone. These synergistic respo nses are inhibited in cells treated with CsA. CsA and FK506 also inhib it the luciferase response to histamine, indicating that histamine can induce NFAT-mediated transcription in HUVEC. To identify candidate ge nes in HUVEC that might be regulated by NFAT, the expression of severa l chemokine mRNAs was measured after histamine treatment. Of the mRNAs tested, only those encoding monocyte chemotactic protein-1 (similar t o 2-fold over basal) and interleukin-8 (similar to 6-fold over basal) are induced by histamine; both of these responses are suppressed by Cs A and FK506. The H-1 histamine receptor antagonist chlorpheniramine, b ut not the H-2 receptor antagonist ranitidine, blocks the effects of h istamine in this preparation. These data provide the first evidence fo r a physiological inducer of NFAT-mediated transcription in endothelia l cells and support the hypothesis that NFAT participates in H-1 hista mine receptor-induced interleukin-8 gene expression.