Contribution of TNF and of LPS in endotoxemic shock in mice. A reappraisal

Abstract

Species of mice have a different sensitivity to LPS. The mechanisms underlying these differences are not clear. We have investigated the contribution of TNF and of LPS in inducing lethality in endotoxemic models using LPSsensitive C57BI/6 and Balb/c mice, OF1 mice with an intermediate sensitivity, and LPS-resistant C3H/HeJ mice. Our observations showed that TNF largely contributed to lethality, since anti-TNF antibodies protected sensitive Balb/c mice from death over a large range of LPS concentrations. OF1 mice were relatively insensitive to LPS and this was associated with a lesser production of TNF. Similarly, OF1 mice had a reduced sensitivity to challenge with recombinant TNF than Balb/c mice. These observations, therefore, indicated that TNF production and sensitivity were determinant for outcome upon LPS challenge. LPS levels were similar in Balb/c, C57BI/6, and OF1 mice, suggesting that a difference in LPS clearance did not contribute to the differences in sensitivity to LPS. The contribution of the combination of both TNF and LPS in endotoxemic shock was investigated with the LPS-resistant C3H/HeJ mice. While these mice were resistant to challenge with either LPS or a low dose of TNF, combination of non lethal concentrations of LPS and TNF induced death. These data, thus, suggest that while TNF is critical for mediating LPS-induced death, the combination of both LPS and TNF act synergistically in contributing to death, particularly in animal species with reduced sensitivity to LPS.