Macrophage cytotoxic factor

TNF-a is also known as cachectin, macrophage cytotoxic factor, macrophage cytotoxin and necrosin. As some of these names suggest, activated macrophages appear to represent the most significant cellular source of TNF-a, but it is also synthesized by many other cell types (Table 9.5). Producer cells do not store TNF-a, but synthesize it de novo following activation. 

Meerpohl HG, Lohmann-Matthes ML, Fischer H (1976) Studies on the activation of mouse bone-marrow derived macrophages by the macrophage cytotoxicity factor (MCF). Eur J Immunol 6 213-217... 

The discovery of the biological significance of nitric oxide (NO) in the mammalian systems stemmed from two lines of investigation that were conducted sqiait from each other. The first line was focused on the mechanism of acetylcholine-induced vascular relaxation in vitro and in vivo by the endothelium-derived relaxing factor, EDRF (Furchgott and Zawadzki, 1980), while the second examined the mechanism of macrophage cytotoxicity (Stuehr and Marietta, 1985 Hibbs et al, 1987). 

Macrophage-activating factor MAF Td cells Macs activates cytotoxicity and proinflammatory actions... 

The compounds tested showed mitogenic effects,i.e. they stimulated lymphocyte proliferation. Astonishingly, a DIVEMA-DNP conjugate did not induce the production of DNP-specific antibodies. Our results suggest that this is due to the formation of DNP-specific active suppressor cells. Using serum free culture media, we could show for the first time that DIVEMA and derivatives stimulate macrophages to release cytotoxic factors into the supernatant. However, no significant release of lytic enzymes was detected. 

DIVEMA and the derivatives tested failed to stimulate endocytosis by macrophages of iZ5I-PVP and 198/ u (colloidal) higher mol. wt. DIVEMA inhibited pinocytosis. We conclude that the only effect of the compounds tested on macrophages is the release of cytotoxic factors into the supernatant. 

Do DIVEMA derivatives stimulate macrophages in vitro, i.e. do they induce the release of lytic enzymes or cytotoxic factors ... 

Schultz eT"al. (21, 22) found that macrophages of DIVEMA-treated mice iFFibited tumour cell proliferation in vitro this means that DIVEMA activates macrophages. The authors did not find cytotoxic factors in the supernatant of these macrophage cultures. 

Release of cytotoxic factors into the supernatant was tested by adding the supernatant of DIVEMA-treated macrophages to cultures of defined amounts of P815 tumour cells and measuring LDH from lysed tumour cells after 24 hr. of incubation. 

Incubation of peritoneal macrophages with 100 xg EPS, followed by cocultivation with Cr-labeled TNFa-sensitive tumor cells (WEHI 164-tumor cells) resulted in a degree of cytotoxicity equivalent to about 10 U MAF (macrophage activating factor) (Tab. 3). 

Drapier,J.C., Wietzerbin, J. and Hibbs, J.B. Jr (1988) Interferon-gamma and tumor necrosis factor induce the L-arginine-dependent cytotoxic effector mechanism in murine macrophages. European Journal of Immunology 18,1587-1592. 

It is well known that high concentrations of LDL, specifically oxidized LDL, are risk factors for coronary artery disease. This fact is explained by the oxidative hypothesis of atherogenesis. According to this hypothesis, the atheroma is formed by foam cells from the vascular subendothelium that derive from macrophages that have picked up previously oxidized LDL in an uncontrolled manner. These lipoproteins are cytotoxic to the endothelium and, in addition, chemotactic to macrophages and monocytes,... 

Wing, E J. et al., Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor alpha and interferon in cancer patients, Blood, 73, 643, 1989. 

---