Co-administration of Antimicrobial Peptides (AMPs) EnhancesToll-like Receptor 4 (TLR4) Antagonist Activity of a Synthetic Glycolipid

This study describes the effect of co-administration of antimicrobial peptides (AMPs) and synthetic glycolipid FP7, active in inhibiting inflammatory cytokine production caused by TLR4 activation and signaling. The co-administration of two LPS-neutralizing peptides (a cecropin A-melittin hybrid peptide and a human cathelicidin) enhances by an order of magnitude the potency of FP7 in blocking the TLR4 signal. Interestingly, this is not an additional effect of LPS neutralization by peptides, since it also occurs when cells are stimulated by the plant lectin phytohemagglutinin (PHA), a non-LPS TLR4 agonist. Our data suggest a dual mechanism of action for the peptides, not exclusively based on LPS binding and neutralization, but also on a direct effect on LPS-binding proteins of the TLR4 receptor complex. NMR experiments in solution show that peptide addition changes the aggregation state of FP7, promoting the formation of larger micelles. These results suggest a relationship between the aggregation state of lipid A-like ligands and the type and intensity of TLR4 response.