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Journal of Endotoxin Research
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A designed TLR4/MD-2 complex to capture LPS

Katharina Brandl

Department of Internal Medicine I, University of Regensburg, Regensburg, Germany, katharina.brandl{at}klinik.uni-regensburg.de

Thomas Glück

Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

Pia Hartmann

Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

Bernd Salzberger

Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

Werner Falk

Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

The family of Toll-like receptors (TLRs) is involved in the defense of an organism to microbial attack. TLR4-induced signaling is involved in infectious diseases, chronic inflammatory diseases and sepsis; therefore, we aimed at modulating TLR4-signaling via ligand-binding soluble receptors. Because recognition of microbial structures shows some species-specific traits, we specifically selected the mouse model for later in vivo studies. We first prepared the N-terminally Flag-tagged mouse (m) recombinant (r) soluble (s) fusion proteins mrsTLR4-IgGFc (T4Fc) and mrsMD-2 in Drosophila melanogaster Schneider 2 (S2) cells. The function of these molecules was tested by inhibition of synthesis of pro-inflammatory cytokines after stimulation of mouse macrophage RAW 264.7 cells with purified lipopolysaccharide (LPS). T4Fc alone had no inhibitory activity; however, a T4Fc/MD-2 complex blocked LPS activity. By analogy with `cytokine traps', we then prepared a designer molecule (LPS-Trap) by fusing MD-2 to the C-terminus of soluble TLR4 via a flexible linker. LPS-Trap significantly inhibited TNF production by LPS-stimulated RAW 264.7 cells. Thus, the T4Fc/MD-2 complex as well as the LPS-Trap blocked LPS activity in vitro and might thus represent a new therapeutic option in sepsis by neutralization of TLR4-activating ligands.

Key Words: Designer molecule • LPS • MD-2 • signaling • soluble TLR4

Journal of Endotoxin Research, Vol. 11, No. 4, 197-206 (2005)
DOI: 10.1177/09680519050110040301
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