This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deiters, U. Articles by Mühlradt, P. F. Search for Related Content PubMed PubMed Citation Articles by Deiters, U. Articles by Mühlradt, P. F.

 Previous Article  |  Next Article 

Infection and Immunity, August 2003, p. 4456-4462, Vol. 71, No. 8
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.8.4456-4462.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 2- and 6-Mediated Stimulation by Macrophage-Activating Lipopeptide 2 Induces Lipopolysaccharide (LPS) Cross Tolerance in Mice, Which Results in Protection from Tumor Necrosis Factor Alpha but in Only Partial Protection from Lethal LPS Doses

Ursula Deiters,^1* Marina Gumenscheimer,² Chris Galanos,² and Peter F. Mühlradt^1,

German Research Centre for Biotechnology, Immunobiology Research Group, D-38124 Braunschweig,¹ Max Planck Institute for Immunobiology, D-79108 Freiburg, Germany²

Received 26 February 2003/ Returned for modification 11 April 2003/ Accepted 6 May 2003

Patients or experimental animals previously exposed to lipopolysaccharide (LPS) become tolerant to further LPS challenge. We investigated the potential of the macrophage-activating lipopeptide 2 (MALP-2) to induce in vivo cross tolerance to tumor necrosis factor alpha (TNF-) and LPS. MALP-2-induced tolerance could be of practical interest, as MALP-2 proved much less pyrogenic in rabbits than LPS. Whereas LPS signals via Toll-like receptor 4 (TLR4), MALP-2 uses TLR2 and TLR6. LPS-mediated cytokine release was studied in mice pretreated with intraperitoneal injections of MALP-2. No biologically active TNF- could be detected in the serum of MALP-2-treated animals when challenged with LPS 24 or 72 h later, whereas suppression of LPS-dependent interleukin (IL)-6 lasted for only 24 h. Protection from lethal TNF- shock was studied in galactosamine-treated mice. Dose dependently, MALP-2 prevented death from lethal TNF- doses in TLR4^-/- but not in TLR2^-/- mice, with protection lasting from 5 to 24 h. To assay protection from LPS, mice were pretreated with MALP-2 doses of up to 10 µg. Five and 24 h later, the animals were simultaneously sensitized and challenged by intravenous coinjection of galactosamine and a lethal dose of 50 ng of LPS. There was only limited protection (four of seven mice survived) when mice were challenged 5 h after MALP-2 pretreatment, and no protection when mice were challenged at later times. The high effectiveness of MALP-2 in suppressing TNF-, the known ways of biological inactivation, and low pyrogenicity make MALP-2 a potential candidate for clinical use.

Editor: S. H. E. Kaufmann

Present address: Research Group Wound Healing, Gründerzentrum, D-38124 Braunschweig, Germany.

This article has been cited by other articles:

• Greis, A., Murgott, J., Rafalzik, S., Gerstberger, R., Hubschle, T., Roth, J. (2007). Characterization of the febrile response induced by fibroblast-stimulating lipopeptide-1 in guinea pigs. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293: R152-R161 [Abstract] [Full Text]  
• Buckley, J. M., Wang, J. H., Redmond, H. P. (2006). Cellular reprogramming by gram-positive bacterial components: a review. J. Leukoc. Biol. 80: 731-741 [Abstract] [Full Text]  
• Hubschle, T., Mutze, J., Muhlradt, P. F., Korte, S., Gerstberger, R., Roth, J. (2006). Pyrexia, anorexia, adipsia, and depressed motor activity in rats during systemic inflammation induced by the Toll-like receptors-2 and -6 agonists MALP-2 and FSL-1. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290: R180-R187 [Abstract] [Full Text]  
• Quintana, F. J., Cohen, I. R. (2005). Heat Shock Proteins as Endogenous Adjuvants in Sterile and Septic Inflammation. J. Immunol. 175: 2777-2782 [Abstract] [Full Text]  
• Weigt, H., Nassenstein, C., Tschernig, T., Muhlradt, P. F., Krug, N., Braun, A. (2005). Efficacy of Macrophage-activating Lipopeptide-2 Combined with Interferon-{gamma} in a Murine Asthma Model. Am. J. Respir. Crit. Care Med. 172: 566-572 [Abstract] [Full Text]  
• Sterns, T., Pollak, N., Echtenacher, B., Mannel, D. N. (2005). Divergence of Protection Induced by Bacterial Products and Sepsis-Induced Immune Suppression. Infect. Immun. 73: 4905-4912 [Abstract] [Full Text]  
• Feterowski, C., Novotny, A., Kaiser-Moore, S., Muhlradt, P. F., Rossmann-Bloeck, T., Rump, M., Holzmann, B., Weighardt, H. (2005). Attenuated pathogenesis of polymicrobial peritonitis in mice after TLR2 agonist pre-treatment involves ST2 up-regulation. Int Immunol 17: 1035-1046 [Abstract] [Full Text]  
• Silverstein, R. (2004). Review: D-Galactosamine lethality model: scope and limitations. Innate Immunity 10: 147-162 [Abstract]