• Mihai G Netea, Leo A B Joosten, Maria Raftogiannis, Evangelos J Giamarellos-Bourboulis, Athina Savva, Maria Mouktaroudi, Marianna Georgitsi, Anastasia Antonopoulou, Frank L van de Veerdonk, and Jos W M van der Meer.
• 4th Department of Internal Medicine, University of Athens, Medical School, 1 Rimini Str, 12462 Athens, Greece. giamarel@ath.forthnet.gr
• Crit Care. 2011 Jan 1;15(1):R27.

IntroductionDown-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).MethodsPeripheral 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.ResultsInhibition 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.ConclusionsThese 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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