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

Jovinge, Stefan
Ares, Mikko P.S.
Kallin, Bengt
Nilsson, Jan

Received September 1, 1995; revision accepted March 22, 1996.
From the Department of Medicine, Karolinska Hospital, King Gustaf Vth Research Institute, Stockholm, Sweden.
Correspondence to Dr Stefan Jovinge, King Gustaf Vth Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail [email protected].

Arteriosclerosis, Thrombosis, & Vascular Biology 16(12):p 1573-1579, December 1996.

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 micro gram/mL Ox-LDL increased 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 dose-dependent manner, with maximal effect at an LDL concentration of 8 micro gram/mL. Addition of TNF-alpha-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-alpha release by Ox-LDL was associated with activation of transcription factor AP-1, whereas the activity of transcription factor nuclear factor-kappa B remained unchanged. These findings suggest that enhanced secretion of TNF-alpha by macrophages exposed to Ox-LDL may be involved in the formation of atherosclerotic lesions. (Arterioscler Thromb Vasc Biol. 1996;16:1573-1579.)