HUMAN MONOCYTES MACROPHAGES RELEASE TNF-ALPHA IN RESPONSE TO OX-LDL/

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 mu g/mL Ox-LDL inc reased expression of tumor necrosis factor-alpha (TNF-alpha) mRNA but had no effect on interleukin-1 beta, platelet-derived growth factor B and heparin-binding epidermal growth factor-like mitogen mRNA levels. Ox-LDL also stimulated monocyte/macrophage release of TNF-alpha in a d ose-dependent manner, with maximal effect at an LDL concentration of 8 mu g/mL. Addition of TNF-alpha-blocking antibodies to conditioned med ium from monocytes/macrophages already exposed to Ox-LDL reduced mitog enic activity by 44.7 +/- 8.4% (P < .005). Stimulation of TNF-alpha re lease by Ox-LDL was associated with activation of transcription factor AP-1, whereas the activity of transcription factor nuclear factor-kap pa B remained unchanged. These findings suggest that enhanced secretio n of TNF-alpha by macrophages exposed to Ox-LDL may be involved in the formation of atherosclerotic lesions.