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 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.

Enhanced Levels of Soluble and Membrane-Bound CD40 Ligand in Patients With Unstable Angina

“…For example, enhanced oxidative stress and oxidized-LDL might also lead to increased CD40L levels and T-cell activation through monocyte activation or direct effects on T cells. 34,35 One may argue that elevated levels of CD40L are a consequence rather than a cause of unstable angina, and our data do not permit any definitive conclusion on this important issue. The marked rise in sCD40L levels after mechanically induced plaque rupture by PTCA may suggest that raised sCD40L levels are a secondary phenomenon.…”

Tumor Necrosis Factor-α-mediated Protein Kinases in Regulation of Scavenger Receptor and Foam Cell Formation on Macrophage

“…In addition, new data show that only the TNF-R1 signaling pathway is important for this action of down-regulation of MSR activity; in contrast, TNF-R2 knockout (p75-null) mice do not show changes in atherosclerosis as compared with wild-type mice. 3 These results suggest that at least TNF-R1 and TNF-R2 must have different signaling pathways, and also the MSR is susceptible to TNF-R1 but not TNF-R2 pathways. Indeed, in our current studies by using agonist anti-TNF-R1 Ab, it specifically activated TNF-R1 but not TNF-R2 as expected (17, 70 -73).…”

“…TNF is produced mainly by activated mononuclear phagocytes, including activated macrophages and T cells (3)(4)(5), in response to inflammation, infection, and various environmental stimulations. TNF exerting a wide array of biological effects is known to be mediated through two distinct surface binding sites, a type I receptor (TNF-R1, p55-60 kDa) expressed on all cell types, and a type II receptor (TNF-R2, p75-80 kDa) expressed primarily on immune cells and macrophages (6).…”

Hyperbaric Oxygen Reduces the Progression and Accelerates the Regression of Atherosclerosis in Rabbits

“…[1][2][3] It has been isolated from atherosclerotic lesions. 4,5 Oxidized LDLs potentiate monocyte-endothelial cell interaction, 6 regulate cytokine expression, 7,8 and stimulate chemotactic factor expression. 9,10 They have also been shown to induce apoptosis in vascular cells.…”