IngentaConnect Differential inductions of TNF- and IGTP, IIGP by structurally di...

Authors: Lapaque, Nicolas¹; Takeuchi, Osamu²; Corrales, Fernando³; Akira, Shizuo²; Moriyon, Ignacio⁴; Howard, Jonathan C.⁵; Gorvel, Jean-Pierre¹

Source: Cellular Microbiology, Volume 8, Number 3, March 2006 , pp. 401-413(13)

Publisher: Blackwell Publishing

Abstract:

Summary

The innate immune system recognizes microbes by characteristic molecules like the Gram-negative lipopolysaccharide (LPS). Lipid A (the LPS bioactive moiety) signals through toll-like receptors (TLRs) to induce pro-inflammatory molecules and small GTPases of the p47 family involved in intracellular pathogen control. We tested TNF-α and p47-GTPase induction in macrophages using classical LPSs [lipid As with glucosamine backbones, ester- and amide-linked C14:0(3-OH) and C12 to C16 in acyloxyacyl groups] of wild type and mutant Escherichia coli and Yersinia species and non-classical LPSs [lipid As with diaminoglucose, ester-linked 3-OH-fatty acids and C28:0(27-OH) and C23:0(29-OH) in acyloxyacyl groups] of plant endosymbionts (Rhizobium), intracellular pathogens (Brucella and Legionella) and phylogenetically related opportunistic bacteria (Ochrobactrum). Classical but not non-classical LPSs efficiently induced TNF-α, IIGP and IGTP p47-GTPase expression. Remarkably, the acyloxyacyl groups in classical LPSs necessary to efficiently induce TNF-α were not necessary to induce p47-GTPases, suggesting that different aspects of lipid A are involved in this differential induction. This was confirmed by using PPDM2, a non-endotoxic lipid A-structurally related synthetic glycolipid. Despite their different bioactivity, all types of LPSs signalled through TLR-4 and not through TLR-2. However, whereas TNF-α induction was myeloid differentiation factor 88 (MyD88)-dependent, that of p47-GTPases occurred via a MyD88-independent pathway. These observations show that different aspects of the LPS pathogen-associated molecular pattern may be triggering different signalling pathways linked to the same TLR. They also reinforce the hypothesis that non-classical lipid As act as virulence factors by favouring the escape from the innate immune system.

Document Type: Research article

DOI: 10.1111/j.1462-5822.2005.00629.x

Affiliations: 1: Centre d'Immunologie INSERM-CNRS-Université Méditerranée, case 906, 13288 Marseille, Cedex 9, France. 2: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita Osaka 565-0871, Japan. 3: Centro de Investigación Médica Aplicada, University of Navarra, Avda. Pío XII, 5531008 Pamplona, Spain. 4: Department of Microbiology, University of Navarra, c/Irunlarrea 1, 31008 Pamplona, Spain. 5: Institute for Genetics, University of Cologne, Zülpicher Strasse 47, D-50674 Cologne, Germany.

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Differential inductions of TNF-α and IGTP, IIGP by structurally diverse classic and non-classic lipopolysaccharides