title: CD14-independent responses induced by a synthetic lipid A mimetic.
abstract: CRX-527 belongs to a new family of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates, which are considered as potential vaccine adjuvants or stand-alone immunotherapeutics to harness innate immune defenses. Since natural lipid A from bacterial LPS depends on membrane-bound (mCD14) or soluble CD14 for its TLR4 ligand activity, we investigated the involvement of both forms of CD14 in the responses elicited by CRX-527. First, we found that CRX-527 induces NF-kappaB and interferon regulatory factor-3 (IRF-3) activation in human embryonic kidney cells transfected with TLR4 and MD-2 genes alone, whereas the responses to LPS require either co-transfection of the gene encoding mCD14 or addition of soluble CD14. We then observed that monocyte-derived DC, which are devoid of mCD14 respond to CRX-527 but not to LPS in serum-free medium. Furthermore, we found that, in contrast to LPS, CRX-527 induces the production of cytokines in whole blood of a patient with paroxysmal nocturnal hemoglobinuria, a disease in which mCD14-dependent responses are defective. Finally, we demonstrated that splenocytes from CD14-deficient mice produce cytokines in response to CRX-527 but not to LPS. We conclude that the lipid A mimetic CRX-527 does not require the CD14 co-receptor to elicit TLR4-mediated responses.
authors.affiliation: Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium.
authors.forename: Amandine
authors.initials: A
authors.lastname: Legat
authors.forename: Séverine
authors.initials: S
authors.lastname: Thomas
authors.forename: Philippe
authors.initials: P
authors.lastname: Hermand
authors.forename: Marcelle
authors.initials: M
authors.lastname: Van Mechelen
authors.forename: Michel
authors.initials: M
authors.lastname: Goldman
authors.forename: Dominique
authors.initials: D
authors.lastname: De Wit
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D032701:Biomimetics; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D008050:Lipid A / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D051218:Lymphocyte Antigen 96 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009943:Organophosphorus Compounds / Q000276:immunology* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000276:immunology; D014162:Transfection
chemical_list: C530112:AGP 527; D000276:Adjuvants, Immunologic; D016207:Cytokines; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D051218:Lymphocyte Antigen 96; D009943:Organophosphorus Compounds; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D005944:Glucosamine