Inhibition of caspase-1 activation in Gram-negative sepsis and experimental endotoxemia.
BACKGROUND
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.
4th Department of Internal Medicine, University of Athens, Medical School, 1 Rimini Str, 12462 Athens, Greece. giamarel@ath.forthnet.gr
Evangelos J
EJ
Giamarellos-Bourboulis
Frank L
FL
van de Veerdonk
Maria
M
Mouktaroudi
Maria
M
Raftogiannis
Anastasia
A
Antonopoulou
Leo A B
LA
Joosten
Peter
P
Pickkers
Athina
A
Savva
Marianna
M
Georgitsi
Jos W M
JW
van der Meer
Mihai G
MG
Netea
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020170:Caspase 1 / Q000378:metabolism*; D061945:Caspase Inhibitors; D015536:Down-Regulation; D019446:Endotoxemia / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006090:Gram-Negative Bacteria / Q000302:isolation & purification; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011446:Prospective Studies; D018805:Sepsis / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology
D061945:Caspase Inhibitors; D053583:Interleukin-1beta; D020170:Caspase 1
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