Ethanol decreases natural killer cell activation but only minimally affects anatomical distribution after administration of polyinosinic:polycytidylic acid: role in resistance to B16F10 melanoma.

Abstract

Natural killer (NK) cells are critical in resistance to B16F10 lung metastases in B6C3F1 mice. Activation of NK cells by polyinosinic:polycytidylic acid (poly I:C; 0.1 mg, intraperitoneally) increases resistance to B16F10 cells. This effect is reduced after administration of ethanol (EtOH; 6 g/kg by oral gavage). The present study was conducted to determine whether decreased resistance is due to alteration of the distribution and/or the activation of NK cells. These parameters were measured in the spleen, lungs, and peripheral blood 4 and 12 hr after EtOH and poly I:C administration. For assessing the time after poly I:C administration during which NK cells are important in resistance to B16F10 cells, anti-NK1.1 antibody was used to deplete NK cells in vivo 48 hr before and 0, 6, 12, and 24 hr after intravenous injection of B16F10 tumor cells. Depletion of NK cells at any time up to 12 hr after B16F10 administration significantly increased the number of tumor nodules in the lungs, but depletion at 24 hr had a smaller effect. Flow cytometry revealed that there was a small but significant increase in the percentage of NK cells in the lungs at 12 hr, which was not changed by EtOH. Corresponding NK cell lytic function in the lungs was increased significantly at both 4 and 12 hr by poly I:C. However, the increase was not significantly different from the naive control value at 4 hr in mice treated with poly I:C plus EtOH, indicating that EtOH decreased activation of NK cells in the lungs at 4 hr. In the spleen, no treatment significantly altered the percentage of NK cells at 4 or 12 hr. However, poly I:C significantly enhanced lytic function, and this enhancement was suppressed by EtOH (by approximately 50%). In the blood, the only significant change in NK cell percentage or lytic activity was an increase in the percentage of NK cells at 12 hr, which was equivalent in the poly I:C and the poly I:C plus EtOH groups. These results demonstrate that EtOH partially abrogates the poly I:C-induced enhancement of resistance to B16F10 cells and that decreased activation of NK cells in the lungs at a critical time early in the response to poly I:C may contribute to this effect. Other parameters could also contribute, but there was little support for an important role for changes in NK cell distribution.