Interleukin-10 counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis.
Neutrophils play a key role in the pathophysiology of septic multiple organ dysfunction syndrome (MODS) through excessive release of toxic granule components and reactive oxygen metabolites with consequent tissue destruction. The increase of senescent neutrophils during sepsis indicates a potential breakdown of autoregulatory mechanisms including apoptotic processes to remove activated neutrophils from inflammatory sites. Therefore, neutrophil apoptosis of patients with severe sepsis and its regulatory mechanisms were investigated. Spontaneous neutrophil apoptosis from patients with severe sepsis was significantly reduced in comparison to healthy individuals. Cytokines detected in the circulation during sepsis (tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma], granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) inhibited neutrophil apoptosis in both groups, though the effect was more distinct in neutrophils from healthy humans. Addition of lipopolysaccharide (LPS) to neutrophils from healthy humans markedly (P < .05) reduced apoptosis which was partially restored through addition of anti-TNF-antibody. Interleukin-10 (IL-10) counteracted (P < .05) inhibition of neutrophil apoptosis induced by LPS, recombinant human (rh) TNF-alpha, rhIFN-gamma, rhG-CSF, and rhGM-CSF, whereas rhIL-4 or rhIL-13 were ineffective. Reduced neutrophil apoptosis during sepsis was concomitant with increased tyrosine phosphorylation, while IL-10 markedly inhibited tyrosine phosphorylation in LPS-stimulated neutrophils. These results identify proinflammatory cytokines and IL-10 as strong regulators of spontaneous neutrophil apoptosis during sepsis. Inhibition as well as acceleration of neutrophil apoptosis seems to be associated with alterations of signal transduction pathways.
Keel
M
M
Department of Surgery, University Hospital Zurich, Zurich, Switzerland.
Ungethüm
U
U
Steckholzer
U
U
Niederer
E
E
Hartung
T
T
Trentz
O
O
Ertel
W
W
D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology / Q000502:physiology*; D009504:Neutrophils / Q000473:pathology* / Q000502:physiology; D018805:Sepsis / Q000097:blood* / Q000473:pathology
D016207:Cytokines; D016753:Interleukin-10