Human Monocytes/Macrophages Release TNF-α in Response to Ox-LDL

Abstract

The uptake of oxidatively modified low density lipoprotein (Ox-LDL) by intimal macrophages is believed to play a key role in the development of atherosclerosis. The present study demonstrates that Ox-LDL in low concentrations activates monocyte/macrophage release of factors that stimulate smooth muscle cell growth, whereas higher concentrations are inhibitory. Exposure of monocytes/macrophages to 8 μg/mL Ox-LDL increased expression of tumor necrosis factor-α (TNF-α) mRNA but had no effect on interleukin-1β, platelet-derived growth factor B and heparin-binding epidermal growth factor–like mitogen mRNA levels. Ox-LDL also stimulated monocyte/macrophage release of TNF-α in a dose-dependent manner, with maximal effect at an LDL concentration of 8 μg/mL. Addition of TNF-α–blocking antibodies to conditioned medium from monocytes/macrophages already exposed to Ox-LDL reduced mitogenic activity by 44.7±8.4% (P<.005). Stimulation of TNF-α release by Ox-LDL was associated with activation of transcription factor AP-1, whereas the activity of transcription factor nuclear factor-κB remained unchanged. These findings suggest that enhanced secretion of TNF-α by macrophages exposed to Ox-LDL may be involved in the formation of atherosclerotic lesions.