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 postop erative sepsis? When, during the septic course, may immunosupression develo p? 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 s urgery and 85 control patients. Monocyte secretion of interleukin (IL)-1 be ta, IL-12 p40 and p70, IL-18, tumor necrosing factor; and IL-IO with or wit hout 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 en dotoxin-stimulated monocyte production of IL-12 p40, IL-10 in both survivin g and nonsurviving patients. During. the final phase of postoperative sepsi s, a significant recovery of IL-12 p40 and IL-IP secretion, but not of IL-1 0 production, correlated with survival. Despite thr exposure of monocytes i n vitro to IFN-gamma for IG hours, the production of the biologically activ e IL-12 p70 heterodimer was severely suppressed both in survivors and nonsu rvivors, although the secretion of the p40 subunit was restored. In contras t, 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 D t low the limits of detection detection in all samples. Conclusions. Postoperative sepsis was associated with immediate monocyte de fects that affected both pro- and anti-inflammatory cytokine secretion, whi ch suggests that immunosuppression is a primary rather than a compensatory response to a septic challenge. Sepsis survival correlated with the recover y of the proinflammatory, but not the anti-ininflammatory, response. The tr eatment of monocytes with IFN-gamma did not reconstitute defective proinfla mmatory cytokine production.