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

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

doi:10.1097/CCM.0b013e318211ff56

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

Tanja Barkhausen, Thomas Tschernig, Philip Rosenstiel, Martijn van Griensven, Ralf-Peter Vonberg, Martina Dorsch, Annika Mueller-Heine, Athena Chalaris, Jürgen Scheller, Stefan Rose-John, Dirk Seegert, Christian Krettek, Georg H Waetzig^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1407-13
Number of pages	7
Journal	Critical Care Medicine
Volume	39
Issue number	6
DOIs	https://doi.org/10.1097/CCM.0b013e318211ff56
Publication status	Published - Jun 2011
Externally published	Yes

Keywords

Animals
Antibodies, Neutralizing/therapeutic use
Disease Models, Animal
Dose-Response Relationship, Drug
Interleukin-6/antagonists & inhibitors
Male
Mice
Mice, Inbred C57BL
Recombinant Fusion Proteins/therapeutic use
Sepsis/drug therapy
Signal Transduction/drug effects

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10.1097/CCM.0b013e318211ff56

Cite this

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., & Waetzig, G. H. (2011). Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Critical Care Medicine, 39(6), 1407-13. https://doi.org/10.1097/CCM.0b013e318211ff56

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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.",

keywords = "Animals, Antibodies, Neutralizing/therapeutic use, Disease Models, Animal, Dose-Response Relationship, Drug, Interleukin-6/antagonists & inhibitors, Male, Mice, Mice, Inbred C57BL, Recombinant Fusion Proteins/therapeutic use, Sepsis/drug therapy, Signal Transduction/drug effects",

author = "Tanja Barkhausen and Thomas Tschernig and Philip Rosenstiel and {van Griensven}, Martijn and Ralf-Peter Vonberg and Martina Dorsch and Annika Mueller-Heine and Athena Chalaris and J{\"u}rgen Scheller and Stefan Rose-John and Dirk Seegert and Christian Krettek and Waetzig, {Georg H}",

year = "2011",

month = jun,

doi = "10.1097/CCM.0b013e318211ff56",

language = "English",

volume = "39",

pages = "1407--13",

journal = "Critical Care Medicine",

issn = "0090-3493",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "6",

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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 & Waetzig, GH 2011, 'Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model', Critical Care Medicine, vol. 39, no. 6, pp. 1407-13. https://doi.org/10.1097/CCM.0b013e318211ff56

TY - JOUR

T1 - Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model

AU - Barkhausen, Tanja

AU - Tschernig, Thomas

AU - Rosenstiel, Philip

AU - van Griensven, Martijn

AU - Vonberg, Ralf-Peter

AU - Dorsch, Martina

AU - Mueller-Heine, Annika

AU - Chalaris, Athena

AU - Scheller, Jürgen

AU - Rose-John, Stefan

AU - Seegert, Dirk

AU - Krettek, Christian

AU - Waetzig, Georg H

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

KW - Animals

KW - Antibodies, Neutralizing/therapeutic use

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Interleukin-6/antagonists & inhibitors

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Recombinant Fusion Proteins/therapeutic use

KW - Sepsis/drug therapy

KW - Signal Transduction/drug effects

U2 - 10.1097/CCM.0b013e318211ff56

DO - 10.1097/CCM.0b013e318211ff56

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C2 - 21336117

SN - 0090-3493

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SP - 1407

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JO - Critical Care Medicine

JF - Critical Care Medicine

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