Anat Katzir Arad

Macrophages (MF) are able to take up effectively oxidized low-density lipoproteins (OxLDL) and become foam cells. OxLDL may stimulate signal transduction pathways of mitogen-activated protein kinases (MAPK) in various mammalian cells, including monocytes/macrophages. These kinases have been implicated in many cellular processes, including proliferation and differentiation. Thus, OxLDL may play an active role in the differentiation of monocytes in the arterial wall and, consequently, in the formation of the atherosclerotic plaque. To assess this hypothesis we studied whether OxLDL could induce THP-1 human monocytes to differentiate into macrophage-like cells; whether MAPK pathways are involved in the OxLDL-induced differentiation process; and which proinflammatory cytokines are induced to be secreted. We found that OxLDL could induce differentiation of THP-1 cells into CD14⁺ macrophage-like cells (OxLDL-MF). NFkB proinflammatory cytokine pathway was inhibited in OxLDL-MF and only the expression and secretion of IL-1b was spared and even enhanced. ERK^MAPK pathway plays a key role in OxLDL-induced THP-1 differentiation as well as in IL-1b expression and secretion. JNK^MAPK pathway plays a role in the up-regulation of IkBa expression and by this may contribute to the inhibition of the NFkB pathway. In vitro inhibition of p38^MAPK could lead to the enhancement of ERK^MAPK stimulation, whereas JNK^MAPK inhibition resulted in a reduction of ERK^MAPK activation and down-regulation of IL-1b expression and secretion. These results point to a cross-talk between the different MAPK pathways in THP-1 cells during OxLDL-induced differentiation. We suggest that OxLDL may induce monocyte differentiation in artery wall and by this may enhance the initiating events of atherogenesis. Localized interference with the specific signaling pathways involved in this process may inhibit or slow the progression of atherosclerosis.