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

Barkhausen, T., Tschernig, T., Rosenstiel, P., van Griensven, M., Vonberg, R. P., Dorsch, M., Mueller-Heine, A., Chalaris, A., Scheller, J., Rose-John, S., Seegert, D., Krettek, C. and Waetzig, G. H. (2011) Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model Critical Care Medicine, 39 (6). pp. 1407-1413. DOI 10.1097/CCM.0b013e318211ff56.

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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. (Crit Care Med 2011; 39: 1407-1413)

Document Type: Article
Keywords: sepsis interleukin-6 sgp130Fc survival apoptosis multiple organ dysfunction systemic inflammatory response soluble receptor leukocyte recruitment epithelial-cells septic mice il-6 levels gp130 apoptosis infection
Research affiliation: Kiel University
Refereed: Yes
DOI etc.: 10.1097/CCM.0b013e318211ff56
ISSN: 0090-3493
Date Deposited: 01 Nov 2012 04:56
Last Modified: 23 Jan 2013 10:01

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