OXIDIZED LOW-DENSITY LIPOPROTEINS AFFECT NATURAL-KILLER-CELL ACTIVITYBY IMPAIRING CYTOSKELETON FUNCTION AND ALTERING THE CYTOKINE NETWORK

Several lines of evidence indicate that oxidative imbalance can play a n important role in determining an impairment of natural killer (NK) c ell activity in a variety of human diseases. Because a specific role f or 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 m odulation. Native LDL served as control. Treatment with ox-LDL at nonc ytotoxic concetrations (0.2 mg/ml) during the NK/target cell (TC) inte raction markedly reduced NK cytotoxic activity against U937 tumor cell s. This inhibitory activity was also noticed when NK cells were pretre ated with ox-LDL. Scanning electron microscopy examination of NK-targe t cell conjugates failed to reveal any morphological cell damage, In a ddition, 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 conjuga tes. By contrast, immunocytochemical analyses of cytoskeleton componen ts of NK cells exposed to ox-LDL showed a partial depolymerization and a derangement of the microtubular apparatus. These alterations were a ccompanied by an evident decrease in their intracellular reduced gluta thione content. Owing to the important role played by the microtubular network during the killing process, it is possible to infer that a cy toskeleton alteration underlies the inhibitory activity of ox-LDL on N K cell function. In addition, exposure of mitogen-stimulated periphera l blood mononuclear cells to ox-LDL markedly reduced specific mRNA tra nscription and release of cytokines relevant for NK cell activity (suc h as tumor necrosis factor-alpha, interferon gamma, and interleukin 12 ). These data suggest that the impairment of NK cell activity by ox-LD L likely reflects the concomitant dysregulation of some essential mech anisms of NK cell function. (C) 1997 Academic Press.