N6-isopentenyladenosine, an endogenous isoprenoid end product, directly affects cytotoxic and regulatory functions of human NK cells through FDPS modulation.
Elena
Ciaglia1, 2*,
Simona
Pisanti1, 2,
Paola
Picardi2,
Chiara
Laezza3,
Anna Maria
Malfitano2,
Alba
D'Alessandro2,
Patrizia
Gazzerro2,
Ennio
Carbone4, 5 and
Maurizio
Bifulco1, 2
-
1
University of Salerno, Medicine and Surgery, Italy
-
2
University of Salerno, Pharmacy, Italy
-
3
IEOS CNR, Institute of Endocrinology and Experimental Oncology, Italy
-
4
University of Catanzaro “Magna Graecia”, Experimental and Clinical Medicine, Italy
-
5
Karolinska Institutet, Microbiology, Tumor and Cell Biology, Sweden
N6-isopentenyladenosine (iPA) is a naturally occurring nucleoside with an isopentenyl moiety derived from mevalonate pathway, and well established anti-tumor activity. In analogy to the unique specificity for phosphoantigens like isopentenyl pyrophosphate (IPP), shown by human Vγ9Vδ2 T cells, here we report for the first time the ability of iPA to selectively expand and directly target human natural killer (NK) cells. Interestingly, submicromolar doses of iPA stimulate resting human NK cells and synergize with IL-2 to induce a their robust activation ex vivo with significant secretion of RANTES and MIP-1α and a large increase in TNF-α and IFN-γ production when compared with IL-2 single cytokine treatment. Moreover iPA promotes NK cell proliferation, upregulates the expression of NK cell activating receptor NKp30, as well as CD69 and CD107a expression. Accordingly this phenotype correlates with significant greater cytotoxicity against tumor targets. At the molecular level, iPA leads to a selective potent activation of MAPK signaling intermediaries downstream IL-2 receptor. The effect results at least in part from the fine modulation of the farnesyl diphosphate synthase (FDPS) activity, the same enzyme implicated in the stimulation of the human γδ T cells. The iPA-driven modulation of FDPS, can cause an enhancement of post-translational prenylation essential for the biological activity of key proteins in NK signaling and effector functions, such as Ras. These unanticipated properties of iPA provide additional piece of evidence of the immunoregulatory role of the intermediates of the mevalonate pathway and open novel therapeutic perspectives for this molecule as an immune modulatory drug.
Acknowledgements
This study was supported by Associazione Italiana Ricerca sul Cancro (AIRC; Investigator Grant IG 13312 to M.B.)
E.Ciaglia was supported by a fellowship from FIRC -Fondazione Italiana Ricerca sul Cancro.
Keywords:
isoprenoids,
NK cells,
Innate immune system,
FDPS,
immunostimulatory signals
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Innate immunity
Citation:
Ciaglia
E,
Pisanti
S,
Picardi
P,
Laezza
C,
Malfitano
A,
D'Alessandro
A,
Gazzerro
P,
Carbone
E and
Bifulco
M
(2013). N6-isopentenyladenosine, an endogenous isoprenoid end product, directly affects cytotoxic and regulatory functions of human NK cells through FDPS modulation..
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00150
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Received:
09 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Elena Ciaglia, University of Salerno, Medicine and Surgery, Baronissi (Salerno), 84081, Italy, eciaglia@unisa.it