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Simultaneous targeting of IL-1 and IL-18 is required for protection against inflammatory and septic shock

Tom Vanden Berghe UGent, Dieter Demon UGent, Pieter Bogaert UGent, Benjamin Vandendriessche, Alain Goethals UGent, Bart Depuydt, Marnik Vuylsteke UGent, Ria Roelandt UGent, Elien Van Wonterghem UGent, Jill Vandenbroecke, et al. (2014) AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 189(3). p.282-291
abstract
Rationale: Sepsis is one of the leading causes of death around the world. The failure of clinical trials to treat sepsis demonstrates that the molecular mechanisms are multiple and are still insufficiently understood. Objectives: To clarify the long disputed hierarchical contribution of several central inflammatory mediators (IL-1 beta, IL-18, caspase [CASP] 7, CASP1, and CASP11) in septic shock and to explore their therapeutic potential. Methods: LPS- and tumor necrosis factor (TNF)-induced lethal shock, and cecal ligation and puncture (CLP) were performed in genetically or pharmacologically targeted mice. Body temperature and survival were monitored closely, and plasma was analyzed for several markers of cellular disintegration and inflammation. Measurements and Main Results: Interestingly, deficiency of both IL-1 beta and IL-18 additively prevented LPS-induced mortality. The detrimental role of IL-1 beta and IL-18 was confirmed in mice subjected to a lethal dose of TNF, or to a lethal CLP procedure. Although their upstream activator, CASP1, and its amplifier, CASP11, are considered potential therapeutic targets because of their crucial involvement in endotoxin-induced toxicity, CASP11- or CASP1/11-deficient mice were not, or hardly, protected against a lethal TNF or CLP challenge. In line with our results obtained in genetically deficient mice, only the combined neutralization of IL-1 and IL-18, using the IL-1 receptor antagonist anakinra and anti-IL-18 antibodies, conferred complete protection against endotoxin-induced lethality. Conclusions: Our data point toward the therapeutic potential of neutralizing IL-1 and IL-18 simultaneously in sepsis, rather than inhibiting the upstream inflammatory caspases.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
GAMMA-INDUCING FACTOR, INTERLEUKIN-1-BETA-DEFICIENT MICE, CONVERTING-ENZYME, IMPROVES SURVIVAL, ESCHERICHIA-COLI, P2X(7) RECEPTOR, ENDOTOXIC-SHOCK, CELL-DEATH, SEPSIS, sepsis, INTERLEUKIN-1 RECEPTOR ANTAGONIST, CASP11, anakinra, IL-18, IL-1
journal title
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Am. J. Respir. Crit. Care Med.
volume
189
issue
3
pages
282 - 291
Web of Science type
Article
Web of Science id
000331793400011
JCR category
RESPIRATORY SYSTEM
JCR impact factor
12.996 (2014)
JCR rank
1/58 (2014)
JCR quartile
1 (2014)
ISSN
1073-449X
DOI
10.1164/rccm.201308-1535OC
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
4349551
handle
http://hdl.handle.net/1854/LU-4349551
date created
2014-04-01 14:14:12
date last changed
2017-06-02 12:18:15
@article{4349551,
  abstract     = {Rationale: Sepsis is one of the leading causes of death around the world. The failure of clinical trials to treat sepsis demonstrates that the molecular mechanisms are multiple and are still insufficiently understood.
Objectives: To clarify the long disputed hierarchical contribution of several central inflammatory mediators (IL-1 beta, IL-18, caspase [CASP] 7, CASP1, and CASP11) in septic shock and to explore their therapeutic potential.
Methods: LPS- and tumor necrosis factor (TNF)-induced lethal shock, and cecal ligation and puncture (CLP) were performed in genetically or pharmacologically targeted mice. Body temperature and survival were monitored closely, and plasma was analyzed for several markers of cellular disintegration and inflammation.
Measurements and Main Results: Interestingly, deficiency of both IL-1 beta and IL-18 additively prevented LPS-induced mortality. The detrimental role of IL-1 beta and IL-18 was confirmed in mice subjected to a lethal dose of TNF, or to a lethal CLP procedure. Although their upstream activator, CASP1, and its amplifier, CASP11, are considered potential therapeutic targets because of their crucial involvement in endotoxin-induced toxicity, CASP11- or CASP1/11-deficient mice were not, or hardly, protected against a lethal TNF or CLP challenge. In line with our results obtained in genetically deficient mice, only the combined neutralization of IL-1 and IL-18, using the IL-1 receptor antagonist anakinra and anti-IL-18 antibodies, conferred complete protection against endotoxin-induced lethality.
Conclusions: Our data point toward the therapeutic potential of neutralizing IL-1 and IL-18 simultaneously in sepsis, rather than inhibiting the upstream inflammatory caspases.},
  author       = {Vanden Berghe, Tom and Demon, Dieter and Bogaert, Pieter and Vandendriessche, Benjamin and Goethals, Alain and Depuydt, Bart and Vuylsteke, Marnik and Roelandt, Ria and Van Wonterghem, Elien and Vandenbroecke, Jill and Choi, Sze Men and Meyer, Evelyne and Krautwald, Stefan and Declercq, Wim and Takahashi, Nozomi and Cauwels, Anje and Vandenabeele, Peter},
  issn         = {1073-449X},
  journal      = {AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE},
  keyword      = {GAMMA-INDUCING FACTOR,INTERLEUKIN-1-BETA-DEFICIENT MICE,CONVERTING-ENZYME,IMPROVES SURVIVAL,ESCHERICHIA-COLI,P2X(7) RECEPTOR,ENDOTOXIC-SHOCK,CELL-DEATH,SEPSIS,sepsis,INTERLEUKIN-1 RECEPTOR ANTAGONIST,CASP11,anakinra,IL-18,IL-1},
  language     = {eng},
  number       = {3},
  pages        = {282--291},
  title        = {Simultaneous targeting of IL-1 and IL-18 is required for protection against inflammatory and septic shock},
  url          = {http://dx.doi.org/10.1164/rccm.201308-1535OC},
  volume       = {189},
  year         = {2014},
}

Chicago
Vanden Berghe, Tom, Dieter Demon, Pieter Bogaert, Benjamin Vandendriessche, Alain Goethals, Bart Depuydt, Marnik Vuylsteke, et al. 2014. “Simultaneous Targeting of IL-1 and IL-18 Is Required for Protection Against Inflammatory and Septic Shock.” American Journal of Respiratory and Critical Care Medicine 189 (3): 282–291.
APA
Vanden Berghe, T., Demon, D., Bogaert, P., Vandendriessche, B., Goethals, A., Depuydt, B., Vuylsteke, M., et al. (2014). Simultaneous targeting of IL-1 and IL-18 is required for protection against inflammatory and septic shock. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 189(3), 282–291.
Vancouver
1.
Vanden Berghe T, Demon D, Bogaert P, Vandendriessche B, Goethals A, Depuydt B, et al. Simultaneous targeting of IL-1 and IL-18 is required for protection against inflammatory and septic shock. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 2014;189(3):282–91.
MLA
Vanden Berghe, Tom, Dieter Demon, Pieter Bogaert, et al. “Simultaneous Targeting of IL-1 and IL-18 Is Required for Protection Against Inflammatory and Septic Shock.” AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 189.3 (2014): 282–291. Print.