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Sci. Signal., 14 February 2012
Vol. 5, Issue 211, p. ra13
[DOI: 10.1126/scisignal.2001963]

RESEARCH ARTICLES

Selective TRIF-Dependent Signaling by a Synthetic Toll-Like Receptor 4 Agonist

William S. Bowen1,2*, Laurie A. Minns1*{dagger}, David A. Johnson1, Thomas C. Mitchell2, Melinda M. Hutton1, and Jay T. Evans1{ddagger}

1 GlaxoSmithKline Biologicals, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
2 Institute for Cellular Therapeutics, University of Louisville School of Medicine, Donald Baxter Biomedical Research Building, 570 South Preston Street, Louisville, KY 40202, USA.

* These authors contributed equally to this work.

{dagger} Present address: Division of Biological Sciences, Bio Research Building, Room 106, The University of Montana, Missoula, MT 59812, USA.

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.

{ddagger} To whom correspondence should be addressed. E-mail: jay.t.evans{at}gskbio.com

Citation: W. S. Bowen, L. A. Minns, D. A. Johnson, T. C. Mitchell, M. M. Hutton, J. T. Evans, Selective TRIF-Dependent Signaling by a Synthetic Toll-Like Receptor 4 Agonist. Sci. Signal. 5, ra13 (2012).

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