Nitric oxide prevents IL-1β and IFN-γ-inducing factor (IL-18) release from macrophages by inhibiting caspase-1 (IL-1β-converting enzyme)

Young Myeong Kim, Robert V. Talanian, Jianrong Li, Timothy R. Billiar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

177 Scopus citations

Abstract

Procytokine processing by caspase-1 is required for the maturation and release of IL-1β and IFN-γ-inducing factor (IGIF) (or IL-18) from activated macrophages (Mφ). 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-1β-converting enzyme (ICE) or caspase-1 activity. Activated RAW264.7 cells released four to five times more IL-1β, but not TNF-α, in the presence of the NO synthase inhibitor N(G)-monomethyl-L- arginine. Stimulated peritoneal Mφ from wild-type mice (inducible NO synthase (iNOS)(+/+)) also released more IL-1β if exposed to N(G)- monomethyl-L-arginine, whereas Mφ 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-1β 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-1β and IFN-γ than their wild-type counterparts at 10 h following LPS injection. Taken together, these data indicate that NO suppresses IL-1β and IGIF processing by inhibiting caspase-1 activity, providing evidence for a unique role for induced NO in regulating IL-1β and IGIF release.

Original languageEnglish
Pages (from-to)4122-4128
Number of pages7
JournalJournal of Immunology
Volume161
Issue number8
StatePublished - 15 Oct 1998
Externally publishedYes

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