Oxidized LDL modulates activation of NFkB in mononuclear phagocytes by altering the degradation of IkBs

Oxidized low density lipoprotein (oxLDL) 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 kB (NFkB), a transcription factor known to be important in controlling the expression of such genes. Pretreatment of peritoneal macrophages with oxLDL modulated the activation of NFkB in response to either lipopolysaccharide (LPS) or the combination of interferon-g (IFN-g) and interleukin-2 (IL2). In macrophages pretreated with oxLDL the nuclear translocation of Rel family members (RelA and c-Rel) is delayed (LPS) or markedly diminished (IFN-g/IL-2) and results in delayed or reduced appearance of kB binding activity within the nucleus. These changes in NFkB activation result from alterations in the stimulus-dependent degradation of IkBa and IkBb. The effects of oxLDL on NFkB 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 IkB/NFkB 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. J. Leukoc. Biol. 64: 667–674; 1998.