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 immunosupression 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-IO 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-10 in both surviving and nonsurviving patients. During. the final phase of postoperative sepsis, a significant recovery of IL-12 p40 and IL-IP secretion, but not of IL-10 production, correlated with survival. Despite thr exposure of monocytes in vitro to IFN-gamma for IG 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 Dt low the limits of detection 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-ininflammatory, response. The treatment of monocytes with IFN-gamma did not reconstitute defective proinflammatory cytokine production.