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Clinical and Vaccine Immunology, September 2008, p. 1309-1315, Vol. 15, No. 9
1071-412X/08/$08.00+0     doi:10.1128/CVI.00060-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Shiri Meron-Sudai,1 Ariella Matityahou,1 Yona Keisari,1 Kathleen H. Cox,2 David L. Hasty,2,3* and Itzhak Ofek1

Department of Human Microbiology, Tel-Aviv University, Ramot-Aviv, Israel 69978,1 Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 800 Madison Avenue, Memphis, Tennessee 38163,2 Research Service (151), Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, Tennessee 381043

Received 13 February 2008/ Returned for modification 2 April 2008/ Accepted 2 July 2008

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 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 ~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, 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).

* Corresponding author. Mailing address: Research Service (151), Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104. Phone: (901) 523-8990, ext. 6456. Fax: (901) 577-7273. E-mail: dhasty{at}utmem.edu

{triangledown} Published ahead of print on 16 July 2008.

Clinical and Vaccine Immunology, September 2008, p. 1309-1315, Vol. 15, No. 9
1071-412X/08/$08.00+0     doi:10.1128/CVI.00060-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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