title: Soluble granzymes are released during human endotoxemia and in patients with severe infection due to gram-negative bacteria.
abstract: Extracellular release of granzymes is considered to reflect the involvement of cytotoxic T lymphocytes and NK cells in various disease states. To obtain insight into granzyme release during bacterial infection, granzyme levels were measured during experimental human endotoxemia and in patients with melioidosis, a severe infection due to gram-negative bacteria. Plasma concentrations of granzyme A (GrA) and GrB increased transiently after endotoxin administration, peaking after 2-6 h. In patients with bacteremic melioidosis, GrA and GrB levels were elevated on admission and remained high during the 72-h study period. In whole blood stimulated with heat-killed Burkholderia pseudomallei, neutralization of tumor necrosis factor, interleukin-12, or interleukin-18 inhibited granzyme secretion, which was independent of interferon-gamma. Stimulation with endotoxin and other gram-negative and gram-positive bacteria also strongly induced the secretion of granzymes, suggesting that granzyme release is a general immune response during bacterial infection. The interaction between the cytokine network and granzymes may play an important immunoregulatory role during bacterial infections.
authors.affiliation: Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. fnlauw@hotmail.com
authors.forename: F N
authors.initials: FN
authors.lastname: Lauw
authors.forename: A J
authors.initials: AJ
authors.lastname: Simpson
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: J M
authors.initials: JM
authors.lastname: Prins
authors.forename: A M
authors.initials: AM
authors.lastname: Wolbink
authors.forename: S J
authors.initials: SJ
authors.lastname: van Deventer
authors.forename: W
authors.initials: W
authors.lastname: Chaowagul
authors.forename: N J
authors.initials: NJ
authors.lastname: White
authors.forename: T
authors.initials: T
authors.lastname: van Der Poll
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016207:Cytokines / Q000378:metabolism*; D019446:Endotoxemia / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count / Q000187:drug effects; D008297:Male; D008554:Melioidosis / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D012697:Serine Endopeptidases / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D013997:Time Factors
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human