INTEGRATING MULTIPLE SIGNALS IN IMMUNE MODULATION

Abstract

Although much is known about the effects of single Toll-like receptor (TLR) activation and downstream signaling, the effect of multiple receptor engagement and how the system integrates individual signals is poorly understood. Interaction between different TLRs is highly plausible as a single pathogen bears multiple pathogen-associated molecular patterns (PAMP), and multiple infectious agents may be present. In this study, combinations of TLR ligands are tested for their effect on cytokine production in macrophages. We have found that the combination of MyD88- and TRIF-utilizing adaptors leads to a synergistic cytokine response when compared to single stimulation controls, at both mRNA and protein levels. Synergistic cytokine production is dependent on new protein synthesis and correlated with sustained ERK phosphorylation, suggesting that synergy acts via inhibition of ERK dephosphorylation, possibly by downregulating DUSP6. Taken together, these findings demonstrate that innate immunity has a degree of discrimination and specificity that has previously been underestimated.