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.