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SUMMARYSynthetic lipopeptides based on bacterial lipoprotein are ef®cient activators for monocytes/ macrophages inducing the release of interleukin (IL)-1, IL-6, tumour necrosis factor-a (TNF-a), reactive oxygen/nitrogen intermediates, and the translocation of nuclear factor kB (NFkB). In this report we investigate the signal transduction pathways involved in leucocyte activation by the synthetic lipopeptide N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)3-lysine (P 3 CSK 4 ). We show that P 3 CSK 4 activates mitogen-activated protein (MAP)-kinases ERK1/2 and MAP kinase (MAPK)-kinases MEK1/2 in bone-marrow-derived macrophages (BMDM) and in the macrophage cell line RAW 264 . 7. Additionally, we could detect differences between the P 3 CSK 4 and lipopolysaccharide (LPS)-induced phosphorylation of MAP kinases: Different levels in phosphorylation were found both in kinetics and dose±response using RAW 264 . 7 cells or BMDM from BALB/c and LPS responder mice (C57BL/10ScSn) or LPS nonresponder mice (C57BL/10ScCr). The lipopeptide activated the MAPK-signalling cascade in both LPS responder and non-responder macrophages, whereas LPS induced the MAPK signalling pathway only in macrophages derived from LPS responder mice. An approximately 70% decrease of lipopeptide induced NFkB translocation and an about 50% reduction of nitric oxide (NO) release was observed in the presence of anti-CD14. These data correspond to the reduction of phosphorylation of ERK1/2 after stimulation with P 3 CSK 4 in the presence of anti-CD14 antibodies. Inhibition of MEK1/2 by PD98059 completely reduced the lipopeptide-induced phosphorylation of ERK1/2 indicating that MEK1/2 are solely responsible for the phosphorylation of the downstream-located MAP kinases ERK1/2.

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