Oxidized low-density lipoproteins affect natural killer cell activity by impairing cytoskeleton function and altering the cytokine network.

Several lines of evidence indicate that oxidative imbalance can play an important role in determining an impairment of natural killer (NK) cell activity in a variety of human diseases. Because a specific role for oxidized low-density lipoproteins (LDL) as pro-oxidizing agents has been envisaged, we tested the activity of oxidized LDL (ox-LDL) on NK cell-mediated cytotoxicity, cytokine release, and membrane molecule modulation. Native LDL served as control. Treatment with ox-LDL at noncytotoxic concentrations (0.2 mg/ml) during the NK/target cell (TC) interaction markedly reduced NK cytotoxic activity against U937 tumor cells. This inhibitory activity was also noticed when NK cells were pretreated with ox-LDL. Scanning electron microscopy examination of NK-target cell conjugates failed to reveal any morphological cell damage. In addition, the number of conjugates and the expression of some adhesion molecules (CD11a, CD11b, CD18, CD2, and CD62L) were not modified by ox-LDL. These observations argued against a possible interference of ox-LDL with the binding process leading to the formation of NK/TC conjugates. By contrast, immunocytochemical analyses of cytoskeleton components of NK cells exposed to ox-LDL showed a partial depolymerization and a derangement of the microtubular apparatus. These alterations were accompanied by an evident decrease in their intracellular reduced glutathione content. Owing to the important role played by the microtubular network during the killing process, it is possible to infer that a cytoskeleton alteration underlies the inhibitory activity of ox-LDL on NK cell function. In addition, exposure of mitogen-stimulated peripheral blood mononuclear cells to ox-LDL markedly reduced specific mRNA transcription and release of cytokines relevant for NK cell activity (such as tumor necrosis factor-alpha, interferon gamma, and interleukin 12). These data suggest that the impairment of NK cell activity by ox-LDL likely reflects the concomitant dysregulation of some essential mechanisms of NK cell function.