Interleukin-1 (IL-1) receptor antagonist prevents Staphylococcus epidermidis-induced hypotension and reduces circulating levels of tumor necrosis factor and IL-1β in rabbits

Abstract

Similar to shock in gram-negative sepsis, shock from gram-positive organisms is mediated, in part, by tumor necrosis factor (TNF) and interleukin-1 (IL-1). In the present study, rabbits were infused with IL-1 receptor antagonist (IL-1ra) prior to and during Staphylococcus epidermidis- induced hypotension. After injection of bacteria, a maximal fall in mean arterial pressure to -42% below baseline occurred at 200 min in vehicle- treated animals compared with a nonsignificant decrease of only 7% in the IL- 1ra-treated group (P < 0.01, vehicle versus IL-1ra). A similar attenuation was observed in the fall in systemic vascular resistance (P < 0.05). After the injection of S. epidermidis, TNF levels rose to a peak elevation of 475 ± 160 U/ml in vehicle-treated rabbits, but in rabbits receiving IL-1ra, maximal TNF levels rose only to 85 ± 23 U/ml (P < 0.01). Plasma IL-1β reached maximal concentrations at 180 min of 364 ± 71 pg/ml in vehicle- treated animals but only 145 ± 12 pg/ml in rabbits given IL-1ra (P < 0.05). The reductions in TNF and IL-1 were not due to interference by IL-1ra in the respective assays. In vitro, IL-1ra inhibited S. epidermidis-induced TNF from mononuclear cells by 31% ± 11%, from spleen cells by 17% ± 4% (P < 0.05), and from whole blood by 42% ± 17%. Despite the near reversal of the fall in mean arterial pressure and systemic vascular resistance in IL-1ra-treated rabbits, leukopenia and thrombocytopenia were unaffected. These results demonstrate that IL-1ra blocks shock-like hemodynamic parameters and reduces circulating IL-1 and TNF levels in a model of gram-positive sepsis.