title: N6-isopentenyladenosine, an endogenous isoprenoid end product, directly affects cytotoxic and regulatory functions of human NK cells through FDPS modulation.
abstract: iPA is a naturally occurring nucleoside with an isopentenyl moiety derived from the mevalonate pathway and a well-established anti-tumor activity. In analogy to the unique specificity for phosphoantigens, such as 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 NK cells. Interestingly, submicromolar doses of iPA stimulate resting human NK cells and synergize with IL-2 to induce a robust activation ex vivo with significant secretion of CCL5 and CCL3 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 and up-regulates the expression of specific NK cell-activating receptors, as well as CD69 and CD107a expression. Accordingly, this phenotype correlates with significantly greater cytotoxicity against tumor targets. At the molecular level, iPA leads to a selective, potent activation of MAPK signaling intermediaries downstream of the IL-2R. The effect results, at least in part, from the fine modulation of the 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 an 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.
authors.affiliation: 1.University of Salerno, Via Salvatore Allende, 84081 Baronissi Salerno, Italy. maubiful@unisa.it or eciaglia@unisa.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Ciaglia
authors.forename: Simona
authors.initials: S
authors.lastname: Pisanti
authors.forename: Paola
authors.initials: P
authors.lastname: Picardi
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Malfitano
authors.forename: Alba
authors.initials: A
authors.lastname: D'Alessandro
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gazzerro
authors.forename: Mario
authors.initials: M
authors.lastname: Vitale
authors.forename: Ennio
authors.initials: E
authors.lastname: Carbone
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000276:immunology; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D051228:Geranyltranstransferase / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007541:Isopentenyladenosine / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D010937:Plant Growth Regulators / Q000276:immunology / Q000494:pharmacology; D017368:Protein Prenylation / Q000502:physiology; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013729:Terpenes / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D051228:Geranyltranstransferase; D007155:Immunologic Factors; D007371:Interferon-gamma; D007376:Interleukin-2; D007541:Isopentenyladenosine; D037181:Lectins, C-Type; D052118:Lysosomal-Associated Membrane Protein 1; D010937:Plant Growth Regulators; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C515429:CCL3 protein, human; C483024:CCL5 protein, human; C573415:IFNG protein, human; C508594:IL2 protein, human
keywords: IFN-γ; MAPK; Ras; cytotoxicity; innate immunity