Differential Induction of Innate Immune Responses by Synthetic Lipid A Derivatives

Recent studies have indicated that lipopolysaccharides (LPS) isolated from particular bacterial strains can bias innate immune responses toward different signal transduction pathways thereby eliciting unique patterns of cytokines. Heterogeneity in the structure of lipid A (the active component of LPS) and possible contaminations with other inflammatory components have made it difficult to confirm these observations and dissect molecular motifs that may be responsible for modulatory properties. To address these issues, we have examined, for the first time, the ability of a range of well defined synthetic lipid As and isolated LPS and lipid A preparations to induce the production of a wide range of cytokines in three different mouse cell types. It was found that, for a given compound, the potencies of production of the various cytokines differed significantly. An additive model, in which a chemical change in the structure of a compound effects the potencies of all cytokines in the same manner, could describe the potencies of the cytokines for all compounds. Thus, no evidence was found that the structure of lipid A can modulate the pattern of cytokine production. In addition, the statistical analysis showed that the relative ordering of the potencies of the compounds was identical in the different cell types and that structural features such as the presence of a 3-deoxy-D-manno-octulosonic acid moiety, anomeric phosphate, lipid length, and acylation pattern were important for pro-inflammatory activity. Finally, it was found that transcriptional and post-transcription control mechanisms determine potencies and efficacies of cytokine production in cell-specific manners.