Soluble granzymes are released during human endotoxemia and in patients with severe infection due to gram-negative bacteria

Extracellular release of granzymes is considered to reflect the involvement of cytotoxic T lymphocytes and NK cells in various disease states. To obta in insight into granzyme release during bacterial infection, granzyme level s were measured during experimental human endotoxemia and in patients with melioidosis, a severe infection due to gram-negative bacteria. Plasma conce ntrations of granzyme A (GrA) and GrB increased transiently after endotoxin administration, peaking after 2-6 h, In patients with bacteremic melioidos is, GrA and GrB levels were elevated on admission and remained high during the 72-h study period. In whole blood stimulated with heat-killed Burkholde ria pseudomallei, neutralization of tumor necrosis factor, interleukin-12, or interleukin-18 inhibited granzyme secretion, which was independent of in terferon-gamma. Stimulation with endotoxin and other gram-negative and gram -positive bacteria also strongly induced the secretion of granzymes, sugges ting that granzyme release is a general immune response during bacterial in fection. The interaction between the cytokine network and granzymes may pla y an important immunoregulatory role during bacterial infections.