Sepsis after major visceral surgery is associated with sustained and interferon-gamma-resistant defects of monocyte cytokine production.
BACKGROUND
Recent clinical trials failed to demonstrate beneficial effects of anti-inflammatory sepsis therapy. The present study therefore asked the following questions: Is there evidence for immunosuppression during postoperative sepsis? When, during the septic course, may immunosuppression develop? Can defective cellular functions be restored by in vitro treatment with interferon-gamma (IFN-gamma)?


METHODS
The study included 35 patients with sepsis after major visceral surgery and 85 control patients. Monocyte secretion of interleukin (IL)-1 beta, IL-12 p40 and p70, IL-18, tumor necrosing factor, and IL-10 with or without IFN-gamma treatment and its correlation with the course and outcome of postoperative sepsis were determined.


RESULTS
Postoperative sepsis was associated with an immediate defect of endotoxin-stimulated monocyte production of IL-12 p40, IL-1 beta, and IL-10 in both surviving and nonsurviving patients. During the final phase of postoperative sepsis, a significant recovery of IL-12 p40 and IL-1 beta secretion, but not of IL-10 production, correlated with survival. Despite the exposure of monocytes in vitro to IFN-gamma for 16 hours, the production of the biologically active IL-12 p70 heterodimer was severely suppressed both in survivors and nonsurvivors, although the secretion of the p40 subunit was restored. In contrast, IFN-gamma treatment resulted in a significant suppression of monocyte IL-1 beta production in all patient subgroups. Alterations of monocyte tumor necrosing factor secretion were not observed. The production of IL-18 was below the limits of detection in all samples.


CONCLUSIONS
Postoperative sepsis was associated with immediate monocyte defects that affected both pro- and anti-inflammatory cytokine secretion, which suggests that immunosuppression is a primary rather than a compensatory response to a septic challenge. Sepsis survival correlated with the recovery of the proinflammatory, but not the anti-inflammatory, response. The treatment of monocytes with IFN-gamma did not reconstitute defective proinflammatory cytokine production.
Weighardt
H
H
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Germany.
Heidecke
C D
CD
Emmanuilidis
K
K
Maier
S
S
Bartels
H
H
Siewert
J R
JR
Holzmann
B
B
D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008297:Male; D009000:Monocytes / Q000276:immunology*; D011183:Postoperative Complications / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014781:Viscera / Q000601:surgery
D016207:Cytokines; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma