Sepsis after major visceral surgery is associated with sustained and interferon-γ–resistant defects of monocyte cytokine production

doi:10.1067/msy.2000.104118

Surgery

Volume 127, Issue 3, March 2000, Pages 309-315

https://doi.org/10.1067/msy.2000.104118 Get rights and content

Abstract

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-γ (IFN-γ)? Methods: The study included 35 patients with sepsis after major visceral surgery and 85 control patients. Monocyte secretion of interleukin (IL)-1β, IL-12 p40 and p70, IL-18, tumor necrosing factor, and IL-10 with or without IFN-γ 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-1β, 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-1β secretion, but not of IL-10 production, correlated with survival. Despite the exposure of monocytes in vitro to IFN-γ 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-γ treatment resulted in a significant suppression of monocyte IL-1β 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-γ did not reconstitute defective proinflammatory cytokine production. (Surgery 2000;127:309-15.)

Section snippets

Patient population and study design

Thirty-five consecutive patients with sepsis who were treated in the surgical intensive care unit were included in the study. Sepsis occurred after major visceral surgery in all patients. The clinical profiles of the patients enrolled in the study are detailed in the Table.Patients with acquired or inherited immunodeficiencies and patients who were receiving immunosuppressive therapy were excluded from the study. For definition of sepsis, established criteria were used. Because of the low

Results

To correlate immune functions with outcome of sepsis, cytokine secretion of adherence-purified monocytes was determined after endotoxin stimulation with or without IFN-γ priming. The overall mortality rate of sepsis was 31% (11/35 patients). The mean postoperative day of sepsis onset did not differ significantly between survivors and nonsurvivors (8.0 ± 1.5 days vs 7.3 ± 1.5 days, respectively). The duration of sepsis was 6.5 ± 0.7 days for survivors and 22.3 ± 6.6 days for nonsurvivors (P

Discussion

In recent models for the immune pathogenesis of sepsis, the initial concepts were extended by the proposal that a compensatory anti-inflammatory reaction is mounted in response to an early state of immune hyperactivity to attenuate the autodestructive potential of proinflammatory mediators. It was further proposed that failure to restore immune balance results in the lethal outcome of sepsis either because of uncontrolled inflammation and cytokine release or because of predominant

Acknowledgements

We thank Martina Rump, Felicitas Altmayr, and Kerstin Weber for expert technical assistance.

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^☆: Supported by grants Si 208/5-1 and Si 208/5-4 from the Deutsche Forschungsgemeinschaft to the clinical research group “Immunsuppression und postoperative Sepsis” and grant H-3-97 from the Kommission für Klinische Forschung, Klinikum rechts der Isar, Technische Universität München.

^☆☆: Reprint requests: Prof Bernhard Holzmann, MD, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str 22, D-81675 Munich, Germany.

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Original CommunicationsSepsis after major visceral surgery is associated with sustained and interferon-γ–resistant defects of monocyte cytokine production☆,☆☆

Abstract

Section snippets

Patient population and study design

Results

Discussion

Acknowledgements

Cell

Immunol Today

Immunity

Immunity

Immunol Today

Lancet

Chest

Chest

Blood

Am J Surg

The instructive role of innate immunity in the acquired immune response

Science

Functional diversity of helper T lymphocytes

Nature

Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+T cells

J Exp Med

Differential CC chemokine-induced enhancement of T helper cell cytokine production

J Immunol

IL-1α and TNF-α are required for IL-12-induced development of Th1 cells producing high levels of IFN-γ in BALB/c but not C57BL/6 mice

J Immunol

Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity

Annu Rev Immunol

The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses

Annu Rev Immunol

Mice Lacking IL-12 develop polarized Th1 cells during viral infection

J Immunol

Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: results from a randomized, double-blind, placebo-controlled trial

JAMA

Treatment of gram-negative bacteremia and septic shock with HA- 1A human monoclonal antibody against endotoxin

N Engl J Med

A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis

JAMA

Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein: the soluble TNF receptor sepsis study group

N Engl J Med

Original Communications
Sepsis after major visceral surgery is associated with sustained and interferon-γ–resistant defects of monocyte cytokine production☆,☆☆

Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4⁺T cells