Cytokine cascade induced by endotoxin in TNF double receptor knockout mice: evidence supporting a role for IL-10 in mediating antipyretic action of TNF

Abstract

Tumor necrosis factor double receptor-knockout (TNFR KO) mice lacking functional genes for the TNF p55 and p75 receptors show exacerbated febrile responses to endotoxin. TNFR KO mice and wild-type (WT) control animals were intraperitoneally treated with 2.5 mg/kg of lipopolysaccharide (LPS), and the effect of this treatment on plasma levels of TNF, interleukin (IL)-6, IL-10 and IL-1 type II (decoy) receptor was studied. TNFR KO mice showed markedly higher levels of TNF 1.5 and 8 h after LPS compared to WT controls. There was no difference in circulatory levels of IL-6 and IL-1 type II receptor between TNFR KO and WT mice 1.5 and 8 h after LPS challenge. There was no difference in plasma IL-10 levels 1.5 h after LPS treatment between TNFR KO and WT mice. However, 8 h after LPS injection TNFR KO mice showed significantly lower levels of IL-10 in plasma than control animals (13.2±2.7 pg/ml vs. 47.6±11.4 pg/ml, P=0.001). These results indicate that under certain conditions the antipyretic action of TNF may be mediated via IL-10 which is considered a major antiinflammatory and antipyretic cytokine. The data obtained also suggest that the exacerbated fever in TNFR KO mice is probably not due to alterations of IL-6 or IL-1 type II (decoy) receptor concentrations in the plasma.