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*
Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia; Università degli Studi di Perugia;
Dipartimento di Farmacologia, Universita’ di Napoli, Italy;
Dipartimento di Medicina Interna, Universita’ di Messina; and
§
NicOx, Sophia Antipolis, France
Caspase-1, the IL-1ß converting enzyme (ICE), is required for
intracellular processing/maturation of IL-1ß and IL-18. NO releasing
nonsteroidal antiinflammatory drugs (NSAIDs) are a new class of NSAID
derivatives that spare the gastric mucosa. Here, we tested the
hypothesis that NCX-4016, a NO-aspirin derivative, inhibits
proinflammatory cytokine release from endotoxin (LPS)-challenged
monocytes. Our results demonstrated that exposing LPS-stimulated human
monocytes to NCX-4016 resulted in a 40–80% inhibition of IL-1ß,
IL-8, IL-12, IL-18, IFN-
, and TNF-
release with an
EC50 of 10–20 µM for IL-1ß and IL-18. Incubating
LPS-primed monocytes with NCX-4016 resulted in intracellular NO
formation as assessed by measuring nitrite/nitrate, intracellular cGMP
concentration, and intracellular NO formation. Exposing LPS-stimulated
monocytes to aspirin or celecoxib caused a 90% inhibition of
prostaglandin E2 generation but had no effect on cytokine
release. NCX-4016, similar to the NO donor
S-nitroso-N-acetyl-D-L-penicillamine,
inhibited caspase-1 activity with an EC50 of 
20 µM.
The inhibition of caspase-1 by NCX-4016 was reversible by the addition
of DTT, which is consistent with S-nitrosylation as the
mechanism of caspase-1 inhibition. NCX-4016, but not aspirin, prevented
ICE activation as measured by assessing the release of ICE p20 subunit.
IL-18 immunoneutralization resulted in a 60–80% reduction of IL-1ß,
IL-8, IFN-, and TNF- release from LPS-stimulated monocytes. Taken
together, these data indicate that incubating human monocytes with
NCX-4016 causes intracellular NO formation and suppresses IL-1ß and
IL-18 processing by inhibiting caspase-1 activity. Caspase-1 inhibition
is a new, cycloxygenase-independent antiinflammatory mechanism of
NO-aspirin.
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