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Eupatilin inhibits T-cell activation by modulation of intracellular calcium flux and NF-kappaB and NF-AT activity.

Abstract
Eupatilin, one of the pharmacologically active ingredients of Artemisia princeps, exhibits a potent anti-ulcer activity, but its effects on T-cell immunity have not been investigated. Here, we show that eupatilin has a profound inhibitory effect on IL-2 production in Jurkat T cells as well as in human peripheral blood leukocytes. Eupatilin neither influenced clustering of CD3 and LFA-1 to the immunological synapse nor inhibited conjugate formation between T cells and B cells in the presence or absence of superantigen (SEE). Eupatilin also failed to inhibit T-cell receptor (TCR) internalization, thereby, suggesting that eupatilin does not interfere with TCR-mediated signals on the membrane proximal region. In unstimulated T cells, eupatilin significantly induced apoptotic cell death, as evidenced by an increased population of annexin V(+)/PI(+) cells and cleavage of caspase-3 and PARP. To our surprise, however, once cells were activated, eupatilin had little effect on apoptosis, and instead slightly protected cells from activation-induced cell death, suggesting that apoptosis also is not a mechanism for eupatilin-induced T-cell suppression. On the contrary, eupatilin dramatically inhibited I-kappaBalpha degradation and NF-AT dephosphorylation and, consequently, inhibited NF-kappaB and NF-AT promoter activities in PMA/A23187-stimulated T cells. Interestingly, intracellular calcium flux was significantly perturbed in cells pre-treated with eupatilin, suggesting that calcium-dependent cascades might be targets for eupatilin action. Collectively, our results provide evidence for dual regulatory functions of eupatilin: (1) a pro-apoptotic effect on resting T cells and (2) an immunosuppressive effect on activated T cells, presumably through modulation of Ca(2+) flux.
AuthorsYoung-Dae Kim, Suck-Chei Choi, Tae-Young Oh, Jang-Soo Chun, Chang-Duk Jun
JournalJournal of cellular biochemistry (J Cell Biochem) Vol. 108 Issue 1 Pg. 225-36 (Sep 1 2009) ISSN: 1097-4644 [Electronic] United States
PMID19565564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright(c) 2009 Wiley-Liss, Inc.
Chemical References
  • Flavonoids
  • Interleukin-2
  • NF-kappa B
  • NFATC Transcription Factors
  • eupatilin
  • Calcium
Topics
  • Apoptosis
  • Calcium (metabolism)
  • Cells, Cultured
  • Flavonoids (pharmacology)
  • Humans
  • Interleukin-2 (metabolism)
  • Jurkat Cells
  • Lymphocyte Activation (drug effects)
  • NF-kappa B (genetics, metabolism)
  • NFATC Transcription Factors (genetics, metabolism)
  • Signal Transduction
  • T-Lymphocytes (metabolism)

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