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

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 chemo- kines, the PAR pathway can be viewed as a mono- nuclear phagocyte-activating principle. Classically, antimicrobial activity of mononuclear phagocytes is the measure for activation. Here, we investigated whether thrombin or SFLLRN-14 increases the an- timicrobial activity of human monocytes and com- pared these effects to those of IFN-. Further- more, 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-. Human monocytes treated with thrombin or SFLLRN-14 and then challenged with Salmonella enterica serovar typhi- murium, including its attenuated mutant phoP ,o r Listeria monocytogenes killed, within 3 h, signif- icantly more bacteria than control cells, an ef- fect comparable with or surpassing the effect of IFN-. 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-, which as expected, increased the secretion of H2O2 by approxi- mately fourfold. Thrombin and SFLLRN-14, but not IFN-, however, significantly increased the antimicrobial activity of acid peptide extracts of monocytes in a radial diffusion assay. Taken to- gether, these findings suggest that IFN- and thrombin differentially regulate oxidative and nonoxidative killing systems of human monocytes. J. Leukoc. Biol. 81: 465-473; 2007.