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J. Biol. Chem., Vol. 282, Issue 18, 13190-13198, May 4, 2007

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Cellular Recognition of Trimyristoylated Peptide or Enterobacterial Lipopolysaccharide via Both TLR2 and TLR4^*

Stephan Spiller, Stefan Dreher, Guangxun Meng, Alina Grabiec, Winston Thomas, Thomas Hartung^¶, Klaus Pfeffer^||, Hubertus Hochrein^**, Helmut Brade, Wolfgang Bessler, Hermann Wagner, and Carsten J. Kirschning¹

From the Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, 81675 Munich, Germany, Deltagen, Inc., San Carlos, California 94025, ^¶European Commission, Joint Research Centre, Institute for Health and Consumer Protection, 21020 Ispra, Italy, ^||Institute of Medical Microbiology, Heinrich-Heine University, 40225 Duesseldorf, Germany, ^**Bavarian Nordic GmbH, 82152 Munich, Germany, the Department of Immune Chemistry and Biochemical Microbiology, Research Center Borstel, 23845 Borstel, Germany, and Institute of Molecular Medicine and Cell Research, Albert-Ludwig University, 79104 Freiburg, Germany

Evidence for specific and direct bacterial product recognition through toll-like receptors (TLRs) has been emphasized recently. We analyzed lipopeptide analogues and enterobacterial lipopolysaccharide (eLPS) for their potential to activate cells through TLR2 and TLR4. Whereas bacterial protein palmitoylated at its N-terminal cysteine and N-terminal peptides derived thereof are known to induce TLR2-mediated cell activation, a synthetic acylhexapeptide mimicking a bacterial lipoprotein subpopulation for which N-terminal trimyristoylation is characteristic (Myr₃CSK₄) activated cells not only through TLR2 but also through TLR4. Conversely, highly purified eLPS triggered cell activation through overexpressed TLR2 in the absence of TLR4 expression if CD14 was coexpressed. Accordingly, TLR2^–/– macrophages prepared upon gene targeting responded to Myr₃CSK₄ challenge, whereas TLR2^–/–/TLR4^d/d cells were unresponsive. Through interferon- (IFN) priming, macrophages lacking expression of functional TLR4 and/or MD-2 acquired sensitivity to eLPS, whereas TLR2/TLR4 double deficient cells did not. Not only TLR2^–/– mice but also TLR4^–/– mice were resistant to Myr₃CSK₄ challenge-induced fatal shock. D-Galactosamine-sensitized mice expressing defective TLR4 or lacking TLR4 expression acquired susceptibility to eLPS-driven toxemia upon IFN priming, whereas double deficient mice did not. Immunization toward ovalbumin using Myr₃CSK₄ as adjuvant was ineffective in TLR2^–/–/TLR4^–/– mice yet effective in wild-type, TLR2^–/–, or TLR4^–/– mice as shown by analysis of ovalbumin-specific serum Ig concentration. A compound such as Myr₃CSK₄ whose stimulatory activity is mediated by both TLR2 and TLR4 might constitute a preferable adjuvant. On the other hand, simultaneous blockage of both of the two TLRs might effectively inhibit infection-induced pathology.

Received for publication, November 6, 2006 , and in revised form, March 7, 2007.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants KI 591/1-5 and SFB/TR22/A5. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1S–6S.

¹ To whom correspondence should be addressed: Institute of Medical Microbiology, Immunology and Hygiene, Technische Universitaet Muenchen, Trogerstr. 30, 81675 Munich, Germany. Tel.: 49-89-4140-4132; Fax: 49-89-4140-4139; E-mail: carsten.kirschning{at}lrz.tum.de.

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