Relationship of tumour necrosis factor and endotoxin to macrophage cytotoxicity, haemorrhagic necrosis and lethal shock.

In this communication we discuss preliminary evidence suggesting a very strong synergism between tumour necrosis factor (TNF) and lipopolysaccharide (LPS) or between TNF and other bacteria in causing haemorrhagic necrosis and lethal shock. We found that TNF by itself does not cause haemorrhagic necrosis when injected into normal skin. TNF also had a rather low systemic toxicity when injected into disease-free, germfree-derived, defined-flora animals. On the other hand the addition of small amounts of LPS markedly raised the lethality of intravenous TNF treatments, and LPS injected into normal skin 'prepared' the site of injection for subsequent induction of haemorrhagic necrosis by locally injected TNF. Similar synergism was observed between TNF and mycoplasma. We suggest that the synergism between TNF and bacterial endotoxin (or other bacteria or bacterial products) may be part of an important defence mechanism against infections which is independent of specific immunity mediated by B and T cells. This synergism may be useful in increasing the therapeutic effects of TNF on tumours if the development of systemic toxicity in this treatment can be prevented.