Triacyl-lipopentapeptide adjuvants: TLR2-dependent activation of macrophages and modulation of receptor-mediated cell activation by altering acyl-moieties.
Synthetic lipopeptides derived from bacterial lipoprotein are efficient immunoadjuvants. In vitro they activate antigen presenting cells (APCs) to induce the translocation of nuclear factor kappa B (NF-kappaB) and the activation of further transcription factors. This results in the expression of genes encoding cytokines such as IL-1, IL-6, TNF-alpha and in the release of reactive oxygen/nitrogen intermediates. The molecular structure of microbial products determines TLR specificity and thus their activatory potential and immunoadjuvanticity. In the present study, we investigated the lipopeptide-induced activation of leukocytes at different cellular levels by applying derivatives of a synthetic lipopentapeptide-fatty acid library. Our results show that TLR2 plays a key role for the activation of bone marrow-derived macrophages (BMDMs) by lipopentapeptide derivatives and that the fatty acid composition of the lipopeptides determines their activation potential and TLR specificity.
Institut für Molekulare Medizin und Zellforschung der Universität, AK Tumorimmunologie/Vakzine, Stefan-Meier-Str. 8, D-79104 Freiburg, Germany.
Silke D C
SD
Müller
Markus R
MR
Müller
Maria
M
Huber
Ulrich v d
Uv
Esche Uv
Carsten J
CJ
Kirschning
H
H
Wagner
Wolfgang G
WG
Bessler
Klaus
K
Mittenbühler
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000737:chemistry*; D008262:Macrophage Activation / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014162:Transfection
D000276:Adjuvants, Immunologic; D001426:Bacterial Proteins; D005231:Fatty Acids, Unsaturated; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019151:Peptide Library; D010455:Peptides; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases