Laboratory Investigations

Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model*

Barkhausen, Tanja PhD; Tschernig, Thomas MD; Rosenstiel, Philip MD; van Griensven, Martijn MD, PhD; Vonberg, Ralf-Peter MD; Dorsch, Martina PhD; Mueller-Heine, Annika Dipl-Stat; Chalaris, Athena PhD; Scheller, Jürgen PhD; Rose-John, Stefan PhD; Seegert, Dirk PhD; Krettek, Christian MD, FRACS, FRCSEd; Waetzig, Georg H. PhD

Author Information

From the Trauma Department (TB, CK), Institute for Medical Microbiology and Hospital Epidemiology (RPV), Central Animal Laboratory (MD), and Institute of Biometry (AMH), Hannover Medical School, Hannover, Germany; Saarland University Hospital (TT), Homburg/Saar, Germany; Institutes of Clinical Molecular Biology (PR) and Biochemistry (AC, SRJ), University of Kiel, Kiel, Germany; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology (MvG), Vienna, Austria; Institute of Biochemistry and Molecular Biology II (JS), University of Düsseldorf, Düsseldorf, Germany; and CONARIS Research Institute AG (DS, GHW), Kiel, Germany.

Supported, in part, by the German Excellence Initiative (Excellence Cluster “Inflammation at Interfaces”).

Dr. Rose-John has stock ownership in CONARIS Research Institute AG and is an inventor on patents owned by CONARIS. Dr. Seegert and Dr. Waetzig are employed by CONARIS Research Institute AG and are inventors on patents owned by CONARIS. The remaining authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: [email protected]

Critical Care Medicine 39(6):p 1407-1413, June 2011. | DOI: 10.1097/CCM.0b013e318211ff56

Abstract

Objective:

The pleiotropic cytokine interleukin (IL)-6 seems to play a pivotal role in sepsis, but contradictory findings in animal models impede a rationale for therapies directed against IL-6. IL-6 signals by two mechanisms via the ubiquitous transmembrane glycoprotein 130 (gp130): “classic” signaling using membrane-bound IL-6 receptor (IL-6R) and trans-signaling using soluble IL-6R (sIL-6R). Trans-signaling is selectively inhibited by soluble gp130 (sgp130). The aim of this study was to systematically compare complete blockade of IL-6 signaling (using a neutralizing anti-IL-6 antibody) and selective blockade of IL-6 trans-signaling (using a fusion protein of sgp130 and the crystallizable fragment of immunoglobulin G1, sgp130Fc) in a standardized cecal ligation and puncture (CLP) sepsis model.

Design:

Animal study.

Setting:

Animal laboratory.

Subjects:

C57BL/6J mice.

Interventions:

We performed a 96-hr dose-response study and a 24-hr study to investigate short-term mechanisms. In the 96-hr study, CLP was performed in 120 randomized mice (20 mice received vehicle, 10 mice per dose group). Mice were treated with equimolar doses of sgp130Fc (0.01/0.1/1/10 mg/kg) or anti-IL-6 (0.008/0.08/0.8/8 mg/kg) 24 hrs before CLP. Two additional groups received 0.5 mg/kg sgp130Fc 24 hrs before or 1 mg/kg sgp130Fc 24 hrs after CLP. Survival and activity scores were obtained daily until 96 hrs after CLP. In the 24-hr study, mice were randomized into four groups with 10 animals each (sham/vehicle, CLP/vehicle, CLP/anti-IL-6 [0.8 mg/kg], and CLP/sgp130Fc [1 mg/kg]) and killed after 24 hrs.

Measurements and Main Results:

In contrast to anti-IL-6, pretreatment with sgp130Fc significantly and dose-dependently increased survival from 45% to 100%. In addition, 1 mg/kg sgp130Fc administered 24 hrs after CLP increased survival from 45% to 80%. Mechanistically, sgp130Fc efficacy was reflected by complete prevention of epithelial cell apoptosis in the jejunum after CLP, which was not achieved with anti-IL-6.

Conclusion:

Selective inhibition of IL-6 trans-signaling by sgp130Fc has considerable potential for the treatment of sepsis and related disorders.

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Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model*