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Clin. Vaccine Immunol. doi:10.1128/CVI.00060-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Lipoteichoic Acid Synergizes with Glycosphingolipids to Potently Stimulate IL-6 Secretion from Human Blood Cells

Department of Human Microbiology, Tel-Aviv University, Ramot-Aviv, Israel 69978; Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 800 Madison Avenue, Memphis, TN 38163; Research Service (151), Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, TN, 38104

^* To whom correspondence should be addressed. Email: dhasty{at}utmem.edu.

	Abstract

In the present study, we found that lipoteichoic acid (LTA) synergizes with glycosphingolipids to stimulate human blood cells to secrete cytokines. We employed globoside, kerasin and lactosylceramide as representative neutral glycosphingolipids and mixed gangliosides, GM₂ and GM₃ as representative acidic glycosphingolipids. LTA and glycosphingolipids enhanced cytokine secretion by human whole blood, peripheral blood mononuclear cells (PBMCs) and purified monocytes, in a dose-dependent manner. The level of synergy ranged up to 10-fold greater than the additive stimulation caused by LTA and glycosphingolipid alone. The greatest synergy was observed with GM₃. We also found that LTA synergizes with the synthetic bacterial lipopeptide mimic, Pam3CysK4. In contrast, glycosphingolipids suppressed stimulation caused by Pam3CysK4. The stimulation of human cells required the simultaneous presence of LTA and the glycosphingolipids and probably requires their physical interactions shown by dot blot and non-denaturing PAGE experiments. We hypothesize that the enhanced stimulation is due to hetero-oligomers between LTA and glycosphingolipids that form at the sub-critical micelle concentrations (sub-CMCs) used in these experiments. Previous studies showed that LTA also synergizes with hemoglobin. The data taken together suggest that LTA may be a pathogen-associated molecular pattern (PAMP), although its full activity requires the presence of a synergistic partner(s).