Synergy between TLR2 and TLR4: a safety mechanism.
BACKGROUND
The Toll (Tlr) receptors facilitate innate immunity by detecting products that are unique to invading microorganisms. Stimulation of these receptors can produce severe reactions and death. We propose that synergy between receptors for different microbial products would provide a safety mechanism, preventing inappropriate, potentially fatal reactions by reacting to low concentrations of ligands when more than a single ligand is present.


RESULTS
Striking synergy is noted between the ligand for Tlr4, lipopolysaccharide (LPS), and a ligand for Tlr2, muramyl dipeptide (MDP), in the release of tumor necrosis factor from RAW cells.


CONCLUSIONS
Synergy between a ligand for Tlr2 and Tlr4 can be demonstrated in a simple in vitro system. The greater sensitivity of MDP-stimulated cells to LPS may explain the data that were once interpreted incorrectly as indicating that Tlr2 is the endotoxin receptor.
Beutler
E
E
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA. beutler@scripps.edu
Gelbart
T
T
West
C
C
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004357:Drug Synergism; D008024:Ligands; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000502:physiology; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D029721:Drosophila Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C048071:endotoxin receptor; D000119:Acetylmuramyl-Alanyl-Isoglutamine