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

Crit Care. 2011;15(1):R27. doi: 10.1186/cc9974. Epub 2011 Jan 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Caspase Inhibitors
  • Interleukin-1beta
  • Caspase 1