Lipoteichoic Acid Synergizes with Glycosphingolipids To Potently Stimulate Secretion of Interleukin-6 from Human Blood Cells

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 GM(2) and GM(3) as representative acidic glycosphingolipids. LTA and the glycosphingolipids enhanced cytokine secretion by human whole blood, peripheral blood mononuclear cells, and purified monocytes in a dose-dependent manner. The level of synergy ranged up to approximately 10-fold greater than the additive stimulation caused by LTA and glycosphingolipid alone. The greatest synergy was observed with GM(3). We also found that LTA synergizes with the synthetic bacterial lipopeptide mimic Pam3CysK4. In contrast, the glycosphingolipids suppressed the stimulation caused by Pam3CysK4. The stimulation of human cells requires the simultaneous presence of LTA and the glycosphingolipids and probably requires their physical interactions, as shown by dot blotting and nondenaturing polyacrylamide gel electrophoresis experiments. We hypothesize that the enhanced stimulation is due to heterooligomers that form between LTA and glycosphingolipids at the subcritical micelle concentrations 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, although its full activity requires the presence of a synergistic partner(s).