In vivo inhibition of lipopolysaccharide-induced lethality and tumor necrosis factor synthesis by Rhodobacter sphaeroides diphosphoryl lipid A is dependent on corticosterone induction.

AUTOR(ES)

Zuckerman, S H

RESUMO

Diphosphoryl lipid A from the lipopolysaccharide (LPS) of Rhodobacter sphaeroides (Rs-DPLA) has been demonstrated to block in mice and guinea pigs the increase in the serum tumor necrosis factor (TNF) response induced by highly purified deep rough chemotype LPS from Escherichia coli D31m4 (ReLPS). The present study was designed to determine the role of corticosterone induction by Rs-DPLA and its effect on TNF regulation and survival in lethal endotoxin shock models and to evaluate the ability of Rs-DPLA to induce endotoxin tolerance. Administration of a 100-fold excess of Rs-DPLA 1 h prior to ReLPS administration inhibited the characteristic peak in serum TNF levels induced by LPS. Inhibition was apparent in normal and D-galactosamine (GalN)-sensitized mice and occurred at the pretranslational level, as splenic TNF and interleukin-1 beta mRNAs were present in lower amounts in LPS-stimulated mice pretreated with Rs-DPLA. Consistent with its effects in reducing serum TNF levels, Rs-DPLA pretreatment protected GalN-sensitized mice from a lethal ReLPS challenge. In contrast, Rs-DPLA did not inhibit the increase in the serum TNF response or protect against a lethal ReLPS challenge in parallel experiments with adrenalectomized (Adrex) mice, for which the 50% lethal dose of ReLPS was comparable to that for GalN-sensitized mice. Furthermore, Rs-DPLA appeared to prime Adrex animals and increase the magnitude of the serum TNF response to a suboptimal LPS stimulus. Priming by Rs-DPLA, however, was not observed in normal or GalN-sensitized mice. Although Rs-DPLA by itself was nontoxic and unable to elevate serum TNF levels in any of the models investigated, it did induce a significant increase in the serum corticosterone response and was capable of inducing endotoxin tolerance in normal mice. The inability of Rs-DPLA to protect Adrex mice from a lethal ReLPS stimulus or to inhibit the increase in the serum TNF response suggests that the protective effect of Rs-DPLA in normal or GalN-sensitized animals occurs through corticosterone induction. These results support the concept that endogenous glucocorticoids can modulate the endotoxic effects of LPS by inhibiting the synthesis of inflammatory cytokines.

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