Synergy between tumor necrosis factor and bacterial products causes hemorrhagic necrosis and lethal shock in normal mice.

We find a strong synergism between tumor necrosis factor (TNF) and bacteria or their products. Endotoxin-"free" recombinant TNF, even at very high doses (160 micrograms), did not alone cause hemorrhagic necrosis (HN) in the skin of normal mice. Similarly, TNF alone had a low systemic toxicity in tumor- and pathogen-free mice. However, TNF given intravenously with nanogram quantities of the endotoxin lipopolysaccharide caused lethal shock. Furthermore, subcutaneous injection of lipopolysaccharide made skin susceptible to subsequent induction of HN by TNF injected in the same site 24 hr later. Mycoplasma-infected cells or corynebacteria also synergized with TNF to cause HN or lethal shock. In addition, we find that lymphotoxin, a cytokine functionally and genetically related to TNF, also synergized with the bacteria to cause HN, whereas interleukin 1 alpha or interferon gamma did not. Together, the results indicate that a synergy between TNF and bacteria or their products causes HN and lethal shock in normal mice.