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

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-1 beta into interleukin-1 beta (IL-1 beta). 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-1 beta in sepsis was more profound than tumour necrosis factor (TNF). Down-regulation of IL-1 beta 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-1 beta in healthy volunteers, an effect that was lost in septic patients. Finally, urate crystals, which specifically induce the NLPR3 inflammasome activation, induced significant IL-1 beta 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 beta production is an important immunological feature in sepsis.