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-Inducing Factor (IL-18) Release from Macrophages by Inhibiting Caspase-1 (IL-1ß-Converting Enzyme)1
*
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261;
Department of Molecular and Cellular Biochemistry, Kangwon National University, Kangwon-do, Chunchon, Korea; and
BASF Bioresearch Corporation, Worcester, MA 01605
Procytokine processing by caspase-1 is required for the maturation
and release of IL-1ß and IFN-
-inducing factor (IGIF) (or IL-18)
from activated macrophages (M
). Nitric oxide (NO) has emerged as a
potent inhibitor of cysteine proteases. Here, we tested the hypothesis
that NO regulates cytokine release by inhibiting IL-1ß-converting
enzyme (ICE) or caspase-1 activity. Activated RAW264.7 cells released
four to five times more IL-1ß, but not TNF-
, in the presence of
the NO synthase inhibitor
NG-monomethyl-L-arginine.
Stimulated peritoneal M from wild-type mice (inducible NO synthase
(iNOS)+/+) also released more IL-1ß if exposed to
NG-monomethyl-L-arginine, whereas M from
iNOS knockout mice (iNOS-/-) did not. Inhibition of NO
synthesis in stimulated RAW264.7 cells also resulted in a threefold
increase in intracellular caspase-1 activity. The NO donor
S-nitroso-N-acetyl-DL-penicillamine
inhibited caspase-1 activity in cells as well as the activity of
purified recombinant caspase-1 and also prevented the cleavage of
pro-IL-1ß and pro-IGIF by recombinant caspase-1. The inhibition of
caspase-1 by NO was reversible by the addition of DTT, which is
consistent with S-nitrosylation as the mechanism of
caspase-1 inhibition. An in vivo role for the regulation of caspase-1
by NO was established in iNOS knockout animals, which exhibited
significantly higher plasma levels of IL-1ß and IFN- than their
wild-type counterparts at 10 h following LPS injection. Taken
together, these data indicate that NO suppresses IL-1ß and IGIF
processing by inhibiting caspase-1 activity, providing evidence for a
unique role for induced NO in regulating IL-1ß and IGIF
release.
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