The Stereochemistry of the Amino Acid Side Chain Influences the Inflammatory Potential of Muramyl Dipeptide in Experimental Meningitis

Abstract

ABSTRACT Intrathecal injections of 50 to 100 μg of ( N -acetylmuramyl- l -alanyl- d -isoglutamine) muramyl dipeptide (MDP)/rabbit dose-dependently triggered tumor necrosis factor alpha (TNF-α) secretion (12 to 40,000 pg/ml) preceding the influx of leukocytes in the subarachnoid space of rabbits. Intrathecal instillation of heat-killed unencapsulated R6 pneumococci produced a comparable leukocyte influx but only a minimal level of preceding TNF-α secretion. The stereochemistry of the first amino acid ( l -alanine) of the MDP played a crucial role with regard to its inflammatory potential. Isomers harboring d -alanine in first position did not induce TNF-α secretion and influx of leukocytes. This stereospecificity of MDPs was also confirmed by measuring TNF-α release from human peripheral mononuclear blood cells stimulated in vitro. These data show that the inflammatory potential of MDPs depends on the stereochemistry of the first amino acid of the peptide side chain and suggest that intact pneumococci and MDPs induce inflammation by different pathways.