Journal of Leukocyte Biology
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(Journal of Leukocyte Biology. 2001;69:590-597.)
© 2001 by Society for Leukocyte Biology

Induction of soluble antitumoral mediators by synthetic analogues of bacterial lipoprotein in bone marrow-derived macrophages from LPS-responder and -nonresponder mice

Silke D. C. Pfannes*, Bernd Müller{dagger}, Stephan Körner{ddagger}, Wolfgang G. Bessler* and Petra Hoffmann*

* Institut für Molekulare Medizin und Zellforschung, AG Tumorimmunologie und Vakzineforschung, and
{dagger} AG Biophysik und Strahlenbiologie, Medizinische Fakultät der Universität Freiburg, 79104 Freiburg, and
{ddagger} Jomol Pharma GmbH, Regensburg, Germany

Correspondence: Silke Pfannes, AG Tumorimmunologie/Vakzine, Institut für Molekulare Medizin und Zellforschung, Stefan-Meier-Strasse 8, D-79104 Freiburg i.Br., Germany. E-mail: pfannes{at}uni-freiburg.de

Macrophage-dependent antitumoral activity is partly mediated by soluble factors including cytokines, reactive-oxygen intermediates (ROIs), and reactive-nitrogen intermediates (RNIs). Activation of macrophages for tumor cytotoxicity can be achieved with various bacterial compounds, such as lipopolysaccharides (LPSs), muramyl-dipeptides, and lipopeptides. We studied the production and release of oxygen radicals, nitric oxide, and tumor necrosis factor {alpha} (TNF-{alpha}) by bone marrow-derived macrophages (BMDMs) of different mouse inbred strains after they were stimulated with the lipopeptide P3CSK4, a water-soluble synthetic analogue of the lipidated N terminus of bacterial lipoprotein. The lipopeptide was able to induce a strong, long lasting release of oxygen radicals in BALB/c mouse macrophages. Furthermore, it induced nitric oxide release from BMDMs of several mouse strains (BALB/c, C57Bl/6, C57Bl/10ScSn, Sv129, NMRI, and LPS-nonresponder C57Bl/10ScCr). Stimulation with P3CSK4 also resulted in comparable production of TNF-{alpha} in LPS-responder and nonresponder BMDMs from C57Bl/10ScSn mice and C57Bl/10ScCr mice, respectively. All three antitumoral mediators reached functional levels or concentrations as shown by the strong cytostatic/cytotoxic activity of lipopeptide-activated macrophages for the cell lines Abelson 8-1, M12.5/P815, and L929, which are sensitive to ROIs, nitric oxide, and TNF-{alpha}, respectively. We found that synthetic lipopeptides can induce the secretion of effective levels of soluble tumor-cytotoxic/cytostatic mediators in BMDMs of LPS-responsive and, of particular interest, also of LPS-unresponsive mice. This result could indicate that the highly effective bacterial-macrophage activators P3CSK4 and LPS use different receptors and/or different intracellular signal transduction pathways.

Key Words: nitric oxide • oxidative burst • tumor necrosis factor-{alpha} • lipopeptide






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