Immunoregulatory effects of progesterone on peripheral blood-derived human NK cells involve down-regulation of NKp46

RAÚL GERMÁN SPALLANZANI; LUCAS EZEQUIEL ROSSI; DAMIÁN EZEQUIEL ÁVILA; DOMAICA, CAROLINA INÉS; ANDREA ZIBLAT; GABRIEL ADRIÁN RABINOVICH; MARIANA SALATINO; NORBERTO WALTER ZWIRNER

Buenos Aires, Argentina

Congreso; 1º Congreso Franco-Argentino de Inmunología; 2010

Sociedad Argentina de Inmunología y French Society of Immunology

Clinical evidence indicates that progesterone Pg and its synthetic analog medroxiprogesterone have pro-tumoraleffects through mechanisms that involve a stimulation of tumor growth and suppressive effects on T cells and dendritic cells,a fact that is relevant during pregnancy but that also could be important during the immune response against tumors, inparticular some of endocrine origin such as mammary tumors. Pg also affects NK cell responsiveness, inducing apoptosisand suppressing IFN-g production of CD56dim cells in response to IL-12. Thus, the aim of this work was to exploreadditional mechanisms by which Pg affects NK cell responsiveness. We assessed the responsiveness of isolated human NKcells stimulated with IL-12, IL-15 and IL-18, a combination of cytokines relevant for NK cell activation. Pg 10-6 M, aconcentration reached in some microenvironments, inhibited IFN-g secretion by cytokine-stimulated NK cells in a19.9±7.8%, as assessed by flow cytometry. Such reduction in IFN-g+ cells was observed in CD56dim and CD56bright NKcells (9.4±5.6% and 8.2±2.9% reduction of IFN-g+ cells, respectively). Pg also inhibited the expression of the NK cellactivating receptors NKp30, NKp46 and NKG2D, as assessed by flow cytometry, as incubation of NK cells with Pg 10-6 Mfor 24 h induced a statistically significant down-regulation of NKp46 (SFI without Pg=13.5±4.0 vs. SFI with Pg=10.8±3.4,n=5, p=0.023). For NKp30 and NKG2D, a down-regulatory effect of Pg was also observed although the differences did notreach statistical significance (NKp30: SFI without Pg=7.6±3.2 vs. SFI with Pg=5.9±2.6; NKG2D: SFI without Pg=10.6±1.8vs. SFI with Pg=8.8±1.4, n=5 for both receptors). Thus, Pg exerts immunosuppressive effects in NK cells that involve adown-regulation of the expression of critical receptors involved in recognition of tumor target cells and the cross-talk withdendritic cells, which may have consequences on their immune surveillance potential.