SELECTIVE MODULATION OF LIPOPOLYSACCHARIDE-INDUCED DEATH AND CYTOKINE PRODUCTION BY VARIOUS MURAMYL PEPTIDES

Pretreatment of animals with the adjuvant muramyl dipeptide enhances both the production of circulating tumor necrosis factor and the sensitivity to the lethal effect of a lipopolysaccharide (LPS) challenge. The present study examined the capacity of various adjuvant muramyl dipeptide derivatives to potentiate responsiveness to LPS administration. Cytokine Levels in serum were determined at various time intervals after LPS administration by bioassays and immunoassays; the cytokines examined were tumor necrosis factor, interleukin-1, interleukin-6, and gamma interferon. The time course of cytokine response was not modified by the pretreatment, but most of the levels were strongly enhanced. However, of the four compounds which were found to be potent priming agents, only two caused an increased sensitivity to LPS lethality, showing that elevated titers of cytokines in serum were not correlated with host sensitization. Interestingly, previous studies have shown that these two compounds also display neurobiological properties, implying a possible role of the central nervous system in LPS lethality. However, two hydrophilic derivatives with low activity as priming agents were capable of decreasing the toxicity of LPS when given after the challenge in galactosamine-sensitized mice. These results illustrate the diversity of responses elicited by immunological priming. They raise unanswered questions on the importance of endogenous mediators in the pathophysiological alterations during toxic shock.