Oxidized LDL modulates activation of NFκB in mononuclear phagocytes by altering the degradation of IκBs

Oxidized low density lipoprotein (ox-LDL) is known to alter the expression of inflammatory gene products in mononuclear phagocytes. The mechanisms involved in this effect were studied by examining the activation of nuclear factor kappa B (NF kappa B), a transcription factor known to be important in controlling the expression of such genes. Pretreatment of peritoneal macrophages with ox-LDL modulated the activation of NF kappa B in response to either lipopolysaccharide (LPS) or the combination of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). In macrophages pretreated with oxLDL the nuclear translocation of Rel family members (RelA and c-Rel) is delayed (LPS) or markedly diminished (IFN-gamma/IL-2) and results in delayed or reduced appearance of kappa B binding activity within the nucleus. These changes in NF kappa B activation result from alterations in the stimulus-dependent degradation of I kappa B alpha and I kappa B beta. The effects of oxLDL on NF kappa B activation depend both on the degree of LDL oxidation (most potent with extensive oxidation) and on the time of exposure of the cells to the lipoprotein preparation (a minimal exposure of 6 h is required before inhibitory effects are observed). The modulation of I kappa B/NF kappa B function in cells exposed to oxLDL appears to be responsible for previously reported effects of oxLDL on chemoattractant cytokine gene expression where both inhibition and delay of such stimulus-dependent events has been observed.