title: Selective TRIF-dependent signaling by a synthetic toll-like receptor 4 agonist.
abstract: In response to ligand binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation-2 (MD-2) receptor complex, two major signaling pathways are activated that involve different adaptor proteins. One pathway depends on myeloid differentiation marker 88 (MyD88), which elicits proinflammatory responses, whereas the other depends on Toll-IL-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF), which elicits type I interferon production. Here, we showed that the TLR4 agonist and vaccine adjuvant CRX-547, a member of the aminoalkyl glucosaminide 4-phosphate (AGP) class of synthetic lipid A mimetics, displayed TRIF-selective signaling in human cells, which was dependent on a minor structural modification to the carboxyl bioisostere corresponding to the 1-phosphate group on most lipid A types. CRX-547 stimulated little or no activation of MyD88-dependent signaling molecules or cytokines, whereas its ability to activate the TRIF-dependent pathway was similar to that of a structurally related inflammatory AGP and of lipopolysaccharide from Salmonella minnesota. This TRIF-selective signaling response resulted in the production of substantially less of the proinflammatory mediators that are associated with MyD88 signaling, thereby potentially reducing toxicity and improving the therapeutic index of this synthetic TLR4 agonist and vaccine adjuvant.
authors.affiliation: GlaxoSmithKline Biologicals, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Bowen
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Minns
authors.forename: David A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Mitchell
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Hutton
authors.forename: Jay T
authors.initials: JT
authors.lastname: Evans
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D008050:Lipid A / Q000494:pharmacology; D015394:Molecular Structure; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C530112:AGP 527; D033942:Adaptor Proteins, Vesicular Transport; C483024:CCL5 protein, human; C114753:CXCL10 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D006835:Hydrazones; D008050:Lipid A; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D016328:NF-kappa B; D009943:Organophosphorus Compounds; C470409:TICAM1 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D005944:Glucosamine