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 micrograms/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 micrograms/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-kB 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.
Jovinge
S
S
Department of Medicine, Karolinska Hospital, King Gustaf Vth Research Institute, Stockholm, Sweden. jovinge@instmed.ks.se
Ares
M P
MP
Kallin
B
B
Nilsson
J
J
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein