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

Pretreatment of animals with the adjuvant muramyl dipeptide enhances b oth the production of circulating tumor necrosis factor and the sensit ivity to the lethal effect of a lipopolysaccharide (LPS) challenge. Th e present study examined the capacity of various adjuvant muramyl dipe ptide derivatives to potentiate responsiveness to LPS administration. Cytokine Levels in serum were determined at various time intervals aft er LPS administration by bioassays and immunoassays; the cytokines exa mined were tumor necrosis factor, interleukin-1, interleukin-6, and ga mma interferon. The time course of cytokine response was not modified by the pretreatment, but most of the levels were strongly enhanced. Ho wever, of the four compounds which were found to be potent priming age nts, only two caused an increased sensitivity to LPS lethality, showin g that elevated titers of cytokines in serum were not correlated with host sensitization. Interestingly, previous studies have shown that th ese 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 challen ge in galactosamine-sensitized mice. These results illustrate the dive rsity of responses elicited by immunological priming. They raise unans wered questions on the importance of endogenous mediators in the patho physiological alterations during toxic shock.