R-form LPS, the master key to the activation of TLR4/MD-2-positive cells

Michael Huber, Christoph Kalis, Simone Keck, Zhengfan Jiang, Philippe Georgel, Xin Du, Louis Shamel, Sosathya Sovath, Suzanne Mudd, Bruce Beutler, Chris Galanos, Marina A. Freudenberg

Research output: Contribution to journalArticle

122 Scopus citations


Lipopolysaccharide (endotoxin, LPS) is a major recognition marker for the detection of gram-negative bacteria by the host and a powerful initiator of the inflammatory response to infection. Using S- and R-form LPS from wild-type and R-mutants of Salmonella and E. coli, we show that R-form LPS readily activates mouse cells expressing the signaling receptor Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), while the S-form requires further the help of the LPS-binding proteins CD14 and LBP, which limits its activating capacity. Therefore, the R-form LPS under physiological conditions recruits a larger spectrum of cells in endotoxic reactions than S-form LPS. We also show that soluble CD14 at high concentrations enables CD14-negative cells to respond to S-form LPS. The presented in vitro data are corroborated by an in vivo study measuring TNF-α levels in response to injection of R- and S-form LPS in mice. Since the R-form LPS constitutes ubiquitously part of the total LPS present in all wild-type bacteria its contribution to the innate immune response and pathophysiology of infection is much higher than anticipated during the last half century.

Original languageEnglish (US)
Pages (from-to)701-711
Number of pages11
JournalEuropean Journal of Immunology
Issue number3
StatePublished - Mar 1 2006


  • CD14
  • Lipopolysaccharide
  • Mast cells
  • TLR4

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Huber, M., Kalis, C., Keck, S., Jiang, Z., Georgel, P., Du, X., Shamel, L., Sovath, S., Mudd, S., Beutler, B., Galanos, C., & Freudenberg, M. A. (2006). R-form LPS, the master key to the activation of TLR4/MD-2-positive cells. European Journal of Immunology, 36(3), 701-711. https://doi.org/10.1002/eji.200535593