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

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.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.These data demonstrate that the inhibition of caspase-1 and defective IL-1 β production is an important immunological feature in sepsis.Despite the increase of our knowledge on the pathophysiology of sepsis, mortality remains high [1]. A vast number of agents aiming to modulate the inflammatory response of the host have failed to provide any clinical benefit [2]. During the initiation of the inflammatory process in sepsis syndrome, microbial components such as lipopolysaccharide (LPS), muramyldipeptide (MDP), flagellin and bacterial DNA interact with pattern recognition receptors (PRRs) that are located either on the cell membrane or in the cytoplasm of host cells. Interaction of these ligands with specific PRRs leads to the activation of a series of intracellular effector molecules and ultimately to nuclear translocation of transcription factors such as of NF-κB (Nuclear Factor kappaB) and subs