Differential inductions of TNF-alpha and IGTP, IIGP by structurally diverse classic and non-classic lipopolysaccharides.
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-alpha 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-alpha, IIGP and IGTP p47-GTPase expression. Remarkably, the acyloxyacyl groups in classical LPSs necessary to efficiently induce TNF-alpha 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-alpha 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.
Centre d'Immunologie INSERM-CNRS-Université Méditerranée, case 906, 13288 Marseille, Cedex 9, France.
Nicolas
N
Lapaque
Osamu
O
Takeuchi
Fernando
F
Corrales
Shizuo
S
Akira
Ignacio
I
Moriyon
Jonathan C
JC
Howard
Jean-Pierre
JP
Gorvel
D000818:Animals; D005260:Female; D020558:GTP Phosphohydrolases / Q000276:immunology* / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008050:Lipid A / Q000737:chemistry / Q000276:immunology; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019081:O Antigens / Q000737:chemistry / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008050:Lipid A; D008070:Lipopolysaccharides; D019081:O Antigens; D014409:Tumor Necrosis Factor-alpha; D020558:GTP Phosphohydrolases; C101131:Igtp protein, mouse; C491070:Iigp1 protein, mouse