SELECTIVE POTENTIATION OF CYTOKINE EXPRESSION IN HUMAN WHOLE-BLOOD BYMURABUTIDE, A MURAMYL DIPEPTIDE ANALOG

Murabutide is a synthetic muramyl peptide which is in clinical stage o f development, Its effect on cytokine production was analysed in human whole blood to reproduce the natural environment, Induced gene transc ription within 2 h was associated with the release of cytokines such a s tumour necrosis factor (TNF), interleukin-l beta (IL-1 beta), IL-6, IL-8, and also the anti-inflammatory mediator IL-1ra. This synthesis w as not associated with the release of IL-4, IL-12, interferon gamma (I FN-gamma), the three colony-stimulating factors (CSFs) or the soluble TNF receptors, The same series of cytokines were assayed to determine the effect of some recombinant cytokines in association with murabutid e, Thus, in the presence of IL-2, IL-6, IL-3 or granulocyte-macrophage colony-stimulating factor (GM-CSF), the level of cytokines induced by murabutide was enhanced with no change in the other cytokines profile , IL-3 and GM-CSF were more potent in increasing the murabutide-induce d response, eliciting synergistic effects on IL-8 and IL-1Ra productio n, at both the mRNA accumulation and the protein release, Although nei ther IL-12 nor IFN-gamma were produced in cells stimulated with murabu tide alone, some mRNA expression was found with combined treatments, T he results indicate that association of murabutide with a cytokine cou ld exert synergistic effects, thus reducing effective doses of the rec ombinant protein, increasing the release of anti-inflammatory mediator s, and triggering efficient cellular immunity. (C) 1996 Academic Press Limited