IL-23 promotes IFN-gamma secretion on human NK cells and primes for IL-18 responsiveness

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

Mar del Plata

Congreso; 62a Reunión Anual de la Sociedad Argentina de Inmunología; 2014

Sociedad Argentina de Inmunología

IL-23 is a member of the IL-12 family of cytokines involved in pro- and anti-tumoral responses. NK cells express IL-23 receptor but the effects of IL-23, mainly produced by dendritic cells (DCs), on human NK cells remain unknown. Previously, we demonstrated that IL-23 induced the secretion of IFN-gamma (IFN-g) but not cytotoxicity of human NK cells against Raji cells. Also, we showed that IL-23 induced a significant up-regulation of CD25 and had a priming effect for IL-18 induced secretion of IFN-g. Therefore, the aim of this work was to further study the role of IL-23 on human NK cells, and the mechanism and signaling pathways underlying the IL-23-induced production of IFN-g. We observed by flow cytometry that IL-23 induced a significant up-regulation of CD69 (p<0.01). Moreover, we observed a significant up-regulation of antibody-dependent cellular cytotoxicity (ADCC) of NK cells against Rituximab (RTX)-coated Raji cells (p<0.05) that was not due to an up-regulation of CD16. Also, using different pharmacological inhibitors (SP600125, AG490, Ly294002, U0126, BAY11-7082, SB-202190, Rapamycin, Fludarabine), we observed that JNK (p<0.001), 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, JAK-STAT3 and STAT-1 pathways were involved in the IL-23-induced secretion of IFN-g (assessed by ELISA). IL-23 induced IFN-g secretion not only by resting but also by activated NK cells (p<0.01). Moreover, we observed that LPS induced the secretion of IL-23 by DCs (p<0.05) while blocking antibodies against IL-23 during DC-NK cell co-cultures induced secretion of significantly lower amounts of IFN-g by NK cells (p<0.05). Overall, our results indicate that IL-23 (alone or in combination with IL-18) exerts a potent stimulatory effect on IFN-g secretion by NK cells, independently of the activation status of the cells. This could be relevant during the cross-talk with DCs and the onset of adaptive immunity.