N6-isopentenyladenosine affects cytotoxic activity and cytokines production by IL-2 activated NK cells and exerts topical anti-inflammatory activity in mice

N6-isopentenyladenosine (iPA) is a modified adenosine with an isopentenyl moiety derived fromthe mevalonate pathway which displays pleiotropic biological effects, including anti-tumor andanti-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 (<1 M) increased the immuneresponse of natural killer (NK) cells against cancer targets. In the present study, we evaluated the effectof iPA at high concentration (10 M) on IL-2-activated NK cells. iPA, inhibited NK cell proliferation andcytotoxicity against their conventional tumor target, human K562 cells. This inhibition was associatedwith decreased expression and functionality of NK cell activating receptors NKp44 and NKG2D as well asimpaired cyto/chemokines secretion (RANTES, MIP-1, TNF- and IFN-). ERK/MAPK and STAT5 activa-tion in IL-2-activated NK cells were inhibited by iPA. The results obtained in vitro were validated in vivoin the inflammatory murine model of croton oil-induced ear dermatitis. The topical application of iPAsignificantly 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 directlytargeting NK cells, providing a novel pharmacological tool in those diseases characterized by a deregulatedimmune-response, such as cancer or inflammatory conditions.