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 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 H(2)O(2) secreted by monocytes. This was in contrast to IFN-gamma, which as expected, increased the secretion of H(2)O(2) 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.
Lippuner
Nadine
N
Research Unit, Clinic for Internal Medicine, AW 9, University Hospital, CH-8091 Zürich, Switzerland.
Morell
Bernhard
B
Schaffner
Andreas
A
Schaer
Dominik J
DJ
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000187:drug effects* / Q000382:microbiology; D010446:Peptide Fragments / Q000494:pharmacology*; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D044463:Receptor, PAR-1; C072032:thrombin receptor peptide (42-55); D003907:Dexamethasone; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D009195:Peroxidase; D013917:Thrombin