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Published on: April 11, 2012
Inhibition of caspase-1 activation in Gram-negative sepsis and experimental endotoxemia
Evangelos J Giamarellos-Bourboulis1, Frank L van de Veerdonk, Maria Mouktaroudi
14th Department of Internal Medicine, University of Athens, Medical School, 1 Rimini Str, 12462 Athens, Greece. giamarel@ath.forthnet.gr
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.
Insights
Sepsis patients show reduced caspase-1 activation, leading to impaired interleukin-1β (IL-1β) production. This defective inflammasome pathway is a key immune characteristic in sepsis, impacting cytokine responses.
Area of Science:
- Immunology
- Molecular Biology
- Critical Care Medicine
Background:
- Sepsis is characterized by dysregulated cytokine production.
- Investigating the mechanisms behind cytokine downregulation, specifically focusing on caspase-1 activation and IL-1β conversion, is crucial for understanding sepsis pathophysiology.
Purpose of the Study:
- To investigate the role of caspase-1 activation and inflammasome function in the impaired interleukin-1β (IL-1β) production observed in sepsis patients.
Main Methods:
- Isolation of peripheral blood mononuclear cells from sepsis patients and healthy volunteers.
- In vitro cytokine stimulation assays with microbial stimuli.
- Assessment of inflammasome activation, caspase-1 activity, and IL-1β production.
Main Results:
- Sepsis patients exhibited profound inhibition of IL-1β compared to TNF.
- Decreased levels of both pro-caspase-1 and activated caspase-1 were observed in sepsis patients.
- Blocking caspase-1 failed to restore IL-1β release in sepsis patients, and NLPR3 inflammasome activation by urate crystals did not induce IL-1β production.
Conclusions:
- Defective caspase-1 activation and subsequent impaired IL-1β production are significant immunological features of sepsis.
- These findings highlight a critical pathway contributing to immune dysregulation in sepsis.
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