Inhibition of caspase-1 activation in Gram-negative sepsis and experimental endotoxemia.

Abstract

INTRODUCTION:

Down-regulation of ex-vivo cytokine production is a specific feature in patients with sepsis. Cytokine downregulation was studied focusing on caspase-1 activation and conversion of pro-interleukin-1β into interleukin-1β (IL-1β).

METHODS:

Peripheral blood mononuclear cells were isolated from a) 92 patients with sepsis mainly of Gram-negative etiology; b) 34 healthy volunteers; and c) 5 healthy individuals enrolled in an experimental endotoxemia study. Cytokine stimulation was assessed in vitro after stimulation with a variety of microbial stimuli.

RESULTS:

Inhibition of IL-1β in sepsis was more profound than tumour necrosis factor (TNF). Down-regulation of IL-1β response could not be entirely explained by the moderate inhibition of transcription. We investigated inflammasome activation and found that in patients with sepsis, both pro-caspase-1 and activated caspase-1 were markedly decreased. Blocking caspase-1 inhibited the release of IL-1β in healthy volunteers, an effect that was lost in septic patients. Finally, urate crystals, which specifically induce the NLPR3 inflammasome activation, induced significant IL-1β production in healthy controls but not in patients with sepsis. These findings were complemented by inhibition of caspase-1 autocleavage as early as two hours after lipopolysaccharide exposure in volunteers.

CONCLUSIONS:

These data demonstrate that the inhibition of caspase-1 and defective IL-1 β production is an important immunological feature in sepsis.

• Authors: Evangelos J Giamarellos-Bourboulis, Frank L van de Veerdonk, Maria Mouktaroudi, Maria Raftogiannis, Anastasia Antonopoulou, Leo A B Joosten, Peter Pickkers, Athina Savva, Marianna Georgitsi, Jos W M van der Meer, Mihai G Netea
• Journal: Critical care (London, England) (Crit Care) Vol. 15 Issue 1 Pg. R27 ( 2011) ISSN: 1466-609X [Electronic] England
• PMID: 21244670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caspase Inhibitors
• Interleukin-1beta
• Caspase 1

Topics

• Adult
• Aged
• Aged, 80 and over
• Caspase 1 (metabolism)
• Caspase Inhibitors
• Down-Regulation
• Endotoxemia (enzymology, metabolism)
• Female
• Gram-Negative Bacteria (isolation & purification)
• Humans
• Interleukin-1beta (metabolism)
• Male
• Middle Aged
• Monocytes (metabolism)
• Prospective Studies
• Sepsis (enzymology, metabolism, microbiology)