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J. Biol. Chem., Vol. 280, Issue 31, 28347-28356, August 5, 2005

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A Lipomannan Variant with Strong TLR-2-dependent Pro-inflammatory Activity in Saccharothrix aerocolonigenes^*

Kevin J. C. Gibson, Martine Gilleron¶, Patricia Constant¶, Bénédicte Sichi¶, Germain Puzo¶, Gurdyal S. Besra||, and Jérôme Nigou¶**

From the School of Bioscience, The University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, the ^¶Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale, CNRS, Unité Mixte de Recherche 5089, 205 Route de Narbonne, 31077 Toulouse cedex 4, France

Lipomannans (LMs) are powerful pro-inflammatory lipoglycans found in mycobacteria and related genera, however the molecular bases of their activity are not fully understood. We report here the isolation and the structural and functional characterization of a new lipomannan variant present in the Pseudonocardineae, Saccharothrix aerocolonigenes, designated SaeLM. Using a range of chemical degradations, NMR experiments, and mass spectrometry analyses, SaeLM revealed a mannosylphosphatidyl-myo-inositol (MPI) anchor glycosylated by an original carbohydrate structure whereby an (16)-Manp backbone is substituted at >80% of the O-2 position by side chains composed of Manp-(12)-Manp-(1. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis indicated a distribution of SaeLM glyco-forms ranging from 19 to 61 Manp units, which centered on species containing 37 or 40 Manp units. SaeLM induced a Toll-like receptor 2 (TLR-2)-dependent production of tumor necrosis factor- (TNF-) by human THP-1 monocyte/macrophage cell lines and interestingly was found to be the strongest inducer of this pro-inflammatory cytokine when compared with other LAM/LM-like molecules. We previously established that a linear (16)-Manp chain, linked to the MPI anchor, is sufficient in providing pro-inflammatory activity. We demonstrate here that by adding side chains and increasing their size, one may potentiate this activity. These findings should enable a better understanding of the structure/function relationships of TLR-2-dependent lipoglycan signaling.

Received for publication, May 19, 2005

^* This work was supported in part by grants from the CNRS (France) (to G. P.). 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.

Present address: Servier Laboratories Ltd., Gallions, Wexham Springs, Wexham, Slough SL3 6RJ, UK.

^|| Supported as a Lister Institute-Jenner Research Fellow and by grants from the Medical Research Council (UK) (Grant G0200510) and the Wellcome Trust (Grant 058972).

^** To whom correspondence should be addressed: Tel: 33-561-175554; Fax: 33-561-175994; E-mail: jerome.nigou{at}ipbs.fr.

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				J. Nigou, T. Vasselon, A. Ray, P. Constant, M. Gilleron, G. S. Besra, I. Sutcliffe, G. Tiraby, and G. Puzo Mannan Chain Length Controls Lipoglycans Signaling via and Binding to TLR2 J. Immunol., May 15, 2008; 180(10): 6696 - 6702. [Abstract] [Full Text] [PDF]