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Published online before print November 9, 2006
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1105634

Received for publication November 6, 2005.
Revised September 12, 2006.
Accepted for publication September 19, 2006.

Article

Proteinase-activated receptors induce nonoxidative, antimicrobial peptides and increased antimicrobial activity in human mononuclear phagocytes

Nadine Lippuner , Bernhard Morell , Andreas Schaffner @, and Dominik J. Schaer

Research Unit, Clinic for Internal Medicine, University Hospital Zürich, Zürich, Switzerland

@ To whom correspondence should be addressed. E-mail: klinsar{at}usz.unizh.ch.


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Abstract

As thrombin and SFLLRNPNDKYEPF (SFLLRN-14), a synthetic ligand, mainly of the proteinase-activated receptor-1 (PAR-1), induce in monocytes the synthesis and secretion of chemokines, the PAR pathway can be viewed as a mononuclear phagocyte-activating principle. Classically, antimicrobial activity of mononuclear phagocytes is the measure for activation. Here, we investigated whether thrombin or SFLLRN-14 increases the antimicrobial activity of human monocytes and compared these effects to those of IFN-{gamma}. Furthermore, we measured the effects of these agents on the secretion of reactive oxygen intermediates and the antimicrobial activity of acid peptide extracts from monocytes. Human monocytes were exposed to maximally active concentrations of thrombin, SFLLRN-14, and IFN-{gamma}. Human monocytes treated with thrombin or SFLLRN-14 and then challenged with Salmonella enterica serovar typhimurium, including its attenuated mutant phoP, or Listeria monocytogenes killed, within 3 h, significantly more bacteria than control cells, an effect comparable with or surpassing the effect of IFN-{gamma}. This finding establishes the proteinase-PAR pathway as a potent, alternate activation pathway of mononuclear phagocytes. Thrombin and SFLLRN-14 had no significant effects on the amount of H2O2 secreted by monocytes. This was in contrast to IFN-{gamma}, which as expected, increased the secretion of H2O2 by approximately fourfold. Thrombin and SFLLRN-14, but not IFN-{gamma}, however, significantly increased the antimicrobial activity of acid peptide extracts of monocytes in a radial diffusion assay. Taken together, these findings suggest that IFN-{gamma} and thrombin differentially regulate oxidative and nonoxidative killing systems of human monocytes.

Key Words: monocytes • oxidative killing • Salmonella




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V. Shpacovitch, M. Feld, M. D. Hollenberg, T. A. Luger, and M. Steinhoff
Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity
J. Leukoc. Biol., June 1, 2008; 83(6): 1309 - 1322.
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