Imperatorin Inhibits T-Cell Proliferation by Targeting the Transcription Factor NFAT

Abstract

In our ongoing research into anti-inflammatory compounds from medicinal plants in the Mediterranean area, we have isolated several furanocoumarins from the roots of Oppopanax chironium (L.), and have evaluated them for activity related to T-cell functionality. Heraclenin (1) and imperatorin (2) significantly inhibited T cell receptor-mediated proliferation in human primary T cells in a concentration-dependent manner. In transient transfection experiments with a plasmid containing the IL-2 promoter we found that imperatorin is a potent inhibitor of IL-2 gene transcription. To further characterize the inhibitory mechanisms of imperatorin at the transcriptional level, we examined the DNA-binding and transcriptional activities of NF-κB, NFAT, and AP-1 transcription factors in Jurkat T cells. We found that imperatorin inhibited both the NFAT binding to DNA and transcriptional activities, without affecting significantly the activation of the NF-κB and AP-1 transcription factors. These findings provide new insights into the molecular mechanisms involved in the immunomodulatory and anti-inflammatory activities of natural furanocoumarins.

Abbreviations

AP-1:activator protein 1

CsA:cyclosporin A

COX-2:cyclooxygenase-2

IL-2:Interleukin 2

NFAT:nuclear factor of activated T cells

NFκB:nuclear factor kappa B

PBCM:peripheral blood mononuclear cells

PMA:phorbol 12-myristate 13-acetate

SEB:staphylococcal enterotoxin B

TCR/CD3:T cell receptor/CD3 complex

Key words

Imperatorin - furanocoumarins - T-cells - NFAT - Oppopanax chironium - Apiaceae

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