ENDOTOXIN TOLERANCE - EFFECTS ON LETHALITY AND MACROPHAGE THROMBOXANE-(B(2)) AND INTERLEUKIN-6 PRODUCTION

The effects of endotoxin pretreatment on induction of in vivo toleranc e to endotoxin lethality, and on in vitro stimulated peritoneal macrop hage mediators, thromboxane (TX)B2 and interleukin 6 (IL-6) were inves tigated. Rats were given i.p. injections of S. enteritidis endotoxin o n days 1 (100 mug/kg) and 2 (500 mug/kg), respectively. After 5 days, or after 2-8 weeks of initial pretreatment, either endotoxin-induced m ortality was assessed, or peritoneal cells were harvested for the in v itro studies. Endotoxin tolerant rats were resistant (p < .05) to endo toxin lethality for 2 weeks after initial induction of tolerance. In v itro studies with peritoneal macrophages demonstrated that endotoxin o r monophosphoryl lipid A stimulated (p < .05) TXB2, production. Howeve r, peritoneal cells harvested from endotoxin tolerant rats exhibited s uppressed (p < .05) TXB2 production to both stimuli which persisted f or at least 8 weeks. Endotoxin stimulated (p < .05) in vitro levels of IL-6 in control cells, but in contrast to the suppressed TXB2 product ion in tolerance, also stimulated (p < .05) in vitro IL-6 in the endot oxin tolerant group. Paradoxically, lipid A did not induce IL-6 produc tion in either group. These composite observations suggest that during endotoxin tolerance neither in vitro peritoneal macrophage TXB2 nor I L-6 synthesis temporally correlate with in vivo resistance to lethalit y.