Cell activation by Toll-like receptors: role of LBP and CD14

Abstract

Members of the Toll-like receptor (TLR) family have been shown to be important in the activation of cells by a variety of microbial ligands. TLRs are thought to mediate the `recognition event' that follows an encounter between a mammalian cell and a microbial agent. In the case of the response to bacterial lipopolysaccharide (LPS), it is clear that the ability of these cell surface proteins to initiate the events necessary for activation of cells to produce cytokines is dependent upon `accessory proteins' such as the pattern recognition protein CD14 and the lipopolysaccharide binding protein (LBP). While the role of these proteins in the LPS-specific response is defined, their role in other TLR responses has not been defined, but it is important in understanding these events and, potentially, in designing new therapeutic strategies. Here we report on the role of these proteins in the response to yeast zymosan. The requirements for this response (which unlike the response to LPS is a response to a particulate antigen) and the role of other serum proteins are defined.

Keywords

Cellular activation lipopolysaccharide inflammatory mediators

References

Lien E. , Ingalls RR Toll-like receptors. Crit Care Med 2002; 30(1 Suppl): S1—S11.

Takeda K. , Kaisho T. , Akira S. Toll-like receptors. Annu Rev Immunol 2003 ; 21: 335—376.

Muta T. , Takeshige K. Essential roles of CD14 and lipopolysaccharide-binding protein for activation of Toll-like receptor (TLR)2 as well as TLR4 reconstitution of TLR2- and TLR4-activation by distinguishable ligands in LPS preparations. Eur J Biochem 2001; 268: 4580—4589.

Hirschfeld M. , Ma Y. , Weis JH , Vogel SN , Weis JJ Repurification of lipopolysaccharide eliminates signaling through both human and murine Toll-like receptor 2. J Immunol 2000; 165: 618—622.

Wurfel MM , Monks BG , Ingalls RR et al. Targeted deletion of the lipopolysaccharide (LPS)-binding protein gene leads to profound suppression of LPS responses ex vivo, whereas in vivo responses remain intact. J Exp Med 1997; 186: 2051—2056.

Tapping RI , Tobias PS Cellular binding of soluble CD14 requires lipopolysaccharide (LPS) and LPS-binding protein. J Biol Chem 1997; 272: 23157—23164.

Schutt C. CD14. Int J Biochem Cell Biol 1998 ; 31: 545—549.

Schutt C. Fighting infection: the role of lipopolysaccharide binding proteins CD14 and LBP. Pathobiology 1999; 67: 227—229.

Heumann D. CD14 and LBP in endotoxemia and infections caused by Gram-negative bacteria . J Endotoxin Res 2001; 7: 439—441.

10.

Underhill DM , Ozinsky A. , Hajjar AM et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 1999; 401: 811—815.

11.

Brown GD , Herre J. , Williams DL , Willment JA , Marshall AS , Gordon S. Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 2003; 197: 1119—1124.

12.

Gantner BN , Simmons RM , Canavera SJ , Akira S. , Underhill DM Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 2003; 197: 1107—1117.