title: N6-isopentenyladenosine affects cytotoxic activity and cytokines production by IL-2 activated NK cells and exerts topical anti-inflammatory activity in mice.
abstract: N6-isopentenyladenosine (iPA) is a modified adenosine with an isopentenyl moiety derived from the mevalonate pathway which displays pleiotropic biological effects, including anti-tumor and anti-angiogenic activity. Previous evidence revealed a biphasic effect of iPA on phytohemagglutinin-stimulated lymphocytes, being pro-proliferative at low doses and anti-proliferative at high doses. Analogously, we have recently shown that low iPA concentrations (<1μM) increased the immune response of natural killer (NK) cells against cancer targets. In the present study, we evaluated the effect of iPA at high concentration (10μM) on IL-2-activated NK cells. iPA, inhibited NK cell proliferation and cytotoxicity against their conventional tumor target, human K562 cells. This inhibition was associated with decreased expression and functionality of NK cell activating receptors NKp44 and NKG2D as well as impaired cyto/chemokines secretion (RANTES, MIP-1α, TNF-α and IFN-γ). ERK/MAPK and STAT5 activation in IL-2-activated NK cells were inhibited by iPA. The results obtained in vitro were validated in vivo in the inflammatory murine model of croton oil-induced ear dermatitis. The topical application of iPA significantly reduced mouse ear oedema, thus suggesting anti-inflammatory properties of this molecule. These results show the ability of iPA to exert anti-inflammatory effects both in vitro and in vivo directly targeting NK cells, providing a novel pharmacological tool in those diseases characterized by a deregulated immune-response, such as cancer or inflammatory conditions.
authors: Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy. Electronic address: eciaglia@unisa.it.
authors: Elena
authors: E
authors: Ciaglia
authors: Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
authors: Simona
authors: S
authors: Pisanti
authors: Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
authors: Paola
authors: P
authors: Picardi
authors: Institute of Endocrinology and Experimental Oncology, IEOS CNR, Via Pansini 5, 80131 Naples, Italy; Department of Biology and Cellular and Molecular Pathology, University of Naples Federico II, Via Pansini, 80131 Naples, Italy.
authors: Chiara
authors: C
authors: Laezza
authors: Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
authors: Silvio
authors: S
authors: Sosa
authors: Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
authors: Aurelia
authors: A
authors: Tubaro
authors: Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy.
authors: Mario
authors: M
authors: Vitale
authors: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
authors: Patrizia
authors: P
authors: Gazzerro
authors: Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
authors: Anna Maria
authors: AM
authors: Malfitano
authors: Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy. Electronic address: maubiful@unisa.it.
authors: Maurizio
authors: M
authors: Bifulco
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D007541:Isopentenyladenosine / Q000008:administration & dosage / Q000494:pharmacology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007376:Interleukin-2; C527085:KLRK1 protein, human; C112837:NCR2 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055629:Natural Cytotoxicity Triggering Receptor 2; D050799:STAT5 Transcription Factor; D007541:Isopentenyladenosine; D020928:Mitogen-Activated Protein Kinases
keywords: Cytotoxicity; ERK; Inflammation; NK cells; STAT5; iPA