Immunostimulation by bacterial components: I. Activation of macrophages and enhancement of genetic immunization by the lipopeptide P3CSK4

Synthetic lipopeptides derived from the N-terminus of bacterial lipoprotein constitute potent macrophage activators and polyclonal B-lymphocyte stimul ators. They are also efficient immunoadjuvants in parenteral, oral and nasa l immunization either in combination with or after covalent linkage to an a ntigen. Here we show how alterations in the molecular structure influence t heir biological properties indicating P3CSK4 as one of the most active memb ers of a lipopentapeptide fatty acid library. This compound resulted in a m ost pronounced macrophage stimulation as indicated by NO release, activatio n of NF kappaB translocation, and enhancement of tyrosine protein phosphory lation. Furthermore, P3CSK4 activates/represses an array of at least 140 ge nes partly involved in signal transduction and regulation of the immune res ponse. Finally we have evidence that P3CSK4 constitutes an effective adjuva nt for DNA immunizations, especially increasing weak humoral immune respons es. Our findings are of importance far further optimizing both conventional and genetic immunization, and for the development of novel synthetic vacci nes. (C) 2000 International Society for Immumopharmacology. published by El sevier Science Ltd. All rights reserved.