Synergistic effects of tumour necrosis factor α and lymphotoxin α during lethal endotoxaemia

Background Tumour necrosis factor (TNF) α and lymphotoxin (LT) α are members of the TNF family which bind to the same receptors and which play a crucial role in the modulation of the immune response. Their differential and possible redundant roles during lethal endotoxaemia have been investigated in mice deficient in either TNF‐α (TNF –/– ) or TNF‐α and LT‐α (TNF –/– LT –/– double knockout) mice. Methods TNF –/– or TNF –/– LT –/– mice were injected intravenously with Escherichia coli lipopolysaccharide (LPS) 1 or 2 mg per mouse. Circulating levels of interleukin (IL) 1α and 1β were measured 3 h after the LPS challenge, and mortality rates were calculated. Results When LPS 1 mg per mouse was used, 80 per cent of the wild‐type mice succumbed, whereas none of the TNF –/– or TNF –/– LT –/– mice died (P < 0·01). However, when LPS 2 mg per mouse was administered, the mortality rate in the control and TNF –/– mice was 100 per cent, whereas none of the TNF –/– LT –/– mice died (P < 0·01), suggesting that the absence of LT‐α has an additional protective effect in lethal endotoxaemia. In comparison to the wild‐type control mice, 3 h after the LPS challenge, the circulating concentrations of IL‐1α were 47 and 55 per cent lower in the TNF –/– and TNF –/– LT –/– mice respectively. Moreover, circulating concentrations of IL‐1β were 40 per cent lower in the TNF –/– mice, but 71 per cent lower in the TNF –/– LT –/– mice compared with the wild‐type controls. Conclusion TNF‐α and LT‐α act synergistically during lethal endotoxaemia, and immunomodulation of both TNF‐α and LT‐α should be considered in experimental and clinical settings. © 2000 British Journal of Surgery Society Ltd