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.
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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)
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Chemical References |
- Caspase Inhibitors
- Interleukin-1beta
- Caspase 1
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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)
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