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J. Biol. Chem., Vol. 279, Issue 10, 8694-8700, March 5, 2004

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Structural Requirements of Synthetic Muropeptides to Synergize with Lipopolysaccharide in Cytokine Induction^*

Stephanie Traub, Niels Kubasch, Siegfried Morath, Matthias Kresse, Thomas Hartung, Richard R. Schmidt, and Corinna Hermann¶

From the Departments of Biochemical Pharmacology and Organic Chemistry, University of Konstanz, Konstanz 78457, Germany

Muropeptides contribute to the recognition of bacteria by modulating immune responses: the structural requirements for adjuvant activity were described in the seventies. During the last years, our knowledge of bacterial pattern recognition has increased dramatically and the importance of the absence of contaminations in both muropeptide preparations and other bacterial stimuli has become clear. We investigated a panel of 15 synthetic Limulus-negative muropeptides, four of them synthesized for the first time, as to their potency to synergize with lipopolysaccharide (LPS) in cytokine induction in human whole blood. No muropeptide was capable of stimulating cytokine release from human blood. However, as little as 20 nM of the muropeptides N-acetyl-muramyl-L-alanyl-D-isoglutamine (muramyl dipeptide, M(ADiQ)), N-acetyl-glucosamine-muramyl dipeptide GM(ADiQ), or C₁₈M(ADiQ), which carries a non-natural additional fatty acid, sufficed to induce an up to 3 log-order shift in tumor necrosis factor -release in response to 100 pg/ml LPS. The release of interleukin-1, interleukin-6, and interleukin-10 was also significantly enhanced although to a lesser extent. The synergistic effect was stereoselective with M(ADiQ) being the minimal active principle. Synergy was also observed on the transcriptional level by means of real-time PCR. Smaller molecules like N-acetylmuramic acid (M), AM, carrying a naturally occurring 1,6-anhydro-bound in M or M(A), containing only the amino acid L-alanine neither synergized with LPS nor influenced the synergy of other muropeptides with LPS. In conclusion, these data show that nanomolar quantities of muropeptides dramatically potentiate LPS-induced monocyte activation. This has implications for pyrogenicity testing and endotoxemia in patients.

Received for publication, September 24, 2003 , and in revised form, December 2, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemical Pharmacology, University of Konstanz; P. O. Box M655, D-78457 Konstanz, Germany. Tel.: 497531884524; Fax: 497531884117; E-mail: Corinna.Hermann{at}uni-konstanz.de.

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