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: Amandine Legat, Séverine Thomas, Philippe Hermand, Marcelle Van Mechelen, Michel Goldman, Dominique De Wit
• Journal: European journal of immunology (Eur J Immunol) Vol. 40 Issue 3 Pg. 797-802 (Mar 2010) ISSN: 1521-4141 [Electronic] Germany
• PMID: 20039305 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AGP 527
• Adjuvants, Immunologic
• Cytokines
• Lipid A
• Lipopolysaccharide Receptors
• Lymphocyte Antigen 96
• Organophosphorus Compounds
• TLR4 protein, human
• Toll-Like Receptor 4
• Glucosamine

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• Biomimetics
• Cell Line
• Cytokines (biosynthesis, immunology)
• Dendritic Cells (drug effects, immunology)
• Glucosamine (analogs & derivatives, immunology, pharmacology)
• Humans
• Lipid A (immunology)
• Lipopolysaccharide Receptors (immunology)
• Lymphocyte Antigen 96 (biosynthesis, immunology)
• Mice
• Mice, Inbred C57BL
• Organophosphorus Compounds (immunology, pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (immunology)
• Toll-Like Receptor 4 (biosynthesis, immunology)
• Transfection