IL-27 promotes IFN-gamma secretion and cytotoxicity of human NK cells

ZIBLAT, ANDREA; DOMAICA, CAROLINA INÉS; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; SPALLANZANI, RAÚL GERMÁN; FUERTES, MERCEDES BEATRIZ; ZWIRNER, NORBERTO WALTER

Los Cocos

Congreso; 61a Reunión Anual de la Sociedad Argentina de Inmunología; 2013

Sociedad Argentina de Inmunología

NK cells express IL-27 receptor but the effects of IL-27, mainly produced by dendritic cells (DCs), on human NK cells remain unknown. Previously we demonstrated that IL-27 induced the secretion of IFN-g and that it also had a priming effect for IL-18. Moreover, IL-27 induced a significant up-regulation of CD69 and NKp46. Accordingly, IL-27 stimulated NKp46-dependent cytotoxicity against Raji cells either alone or in combination with IL-18 through the secretory and TRAIL pathways. Therefore, the aim of this work was to further study the mechanisms and signaling pathways underlying the cytotoxicity and IFN-g secretion induced by IL-27. We observed by flow cytometry with CFSE-labeled target cells, 7-AAD staining, and blocking antibodies, that the Fas-FasL pathway was not involved in the cytotoxicity mentioned above, and that IFN-g was responsible for the increased cytotoxicity observed when NK cells were stimulated with IL-18+IL-27 (p<0.01). Using different inhibitors (SP600125, AG490, Ly294002, U0126, BAY11-7082, SB-202190, Rapamycin) we observed that NF-kB (p<0.001) and m-TOR (p<0.001) pathways were involved in the up regulation of NKp46 on NK cells stimulated with IL-27, and thus in NKp46-mediated cytotoxicity (p<0.05 and p<0.001 respectively). The JNK (p<0.01), PI3K (p<0.01), MEK1/2 (p<0.01), NF-kB (p<0.01) and m-TOR (p<0.001) but not the p38 MAP kinase and JAK-STAT3 pathways were involved in the IL-27-induced secretion of IFN-g (assessed by ELISA). Our results constitute the first description of the signaling pathways that regulate the expression of NKp46. Also, we demonstrate that the signaling pathways involved in the cytotoxicity and secretion of IFN-g induced by IL-27 are partially overlapped. Overall, our results indicate that IL-27 (alone or in combination with IL-18) exerts a potent stimulatory effect on NK cell effector functions, which could be relevant during the cross-talk with DCs and elimination of tumor and virus-infected cells.