ALTERED INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR PRODUCTION AND SECRETION DURING PYROGENIC TOLERANCE TO LPS IN RABBITS

Rabbits were injected intravenously with 10 mu g/kg of endotoxin [lipo polysaccharide (LPS)] on days 0, 1, and 7, and rectal temperatures wer e monitored. The febrile responses were compared with circulating leve ls of interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF) a nd in vitro synthesis of these cytokines by peripheral blood mononucle ar cells (PBMC) isolated just before the injection of LPS. Fever after the first LPS injection was biphasic on day 0, attenuated and monopha sic after the second LPS injection on day 1, and augmented after third injection of LPS on day 7. On day 1, circulating TNF and IL-1 beta le vels were significantly (P < 0.05) decreased compared with those on da ys 0 and 7. Similarly, TNF and IL-1 beta synthesis by LPS-stimulated P BMC were significantly reduced on day 1. On day 7, cellular synthesis and secretion of IL-1 beta were significantly increased compared with that on day 0. A significant positive correlation was observed between fever index and total in vitro IL-1 beta synthesis by LPS-stimulated PBMC (r = 0.866, P = 0.001). These data demonstrate that pyrogenic tol erance in the rabbit after a single LPS injection is associated with d ecreased circulating IL-1 beta and TNF levels as well as decreased pro duction of these cytokines in vitro. In addition, the pyrogenic hyperr esponsiveness to LPS after 7 days is associated with increased synthes is and secretion of IL-1 beta from PBMC in vitro.