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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
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-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. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducing factor (IGIF) (or IL-18)
(6, 7, 8) undergo proteolytic cleavage by caspase-1, permitting the
activated cytokine to exit the cell. Peptide inhibitors of caspase-1
block IL-1ß and IGIF release from activated macrophages (M) in
vitro (8). Caspase-1 knockout (KO) mice fail to exhibit elevations in
IL-1ß, IL-1, and IFN- following an LPS challenge and are
resistant to LPS-induced death (9, 10). Thus, activated caspase-1 is
essential for cytokine processing both in vitro and in vivo.
Caspases exist in cells as zymogens that must themselves undergo
proteolytic activation. Nitric oxide (NO) has recently emerged as a
potent inhibitor of activated caspases (11, 12, 13, 14) and, in hepatocytes, as
an inhibitor of caspase activation (12). NO or an NO reaction product
reversibly inhibits caspase activity by S-nitrosylation at
the active site cysteine (11, 12, 13). S-nitrosylation of
caspase-3-like proteases accounts in part for the capacity of NO to
inhibit apoptosis both in vitro (12, 13, 14, 15) and in vivo (12). These
profound influences of NO on cell viability mediated by NO-caspase
interaction suggest that NO could also down-regulate cytokine
processing through the inhibition of caspase-1. We report here that NO
suppresses M caspase-1 activity and inhibits the release of IL-1ß
protein and IGIF activity in vitro and in vivo. The key role of the
inducible NO synthase (iNOS) (or NOS-2) in the regulation of cytokine
processing is demonstrated in iNOS-deficient animals, which exhibit
exaggerated IL-1ß and IFN- levels in response to LPS. These
results indicate a novel regulatory mechanism for the down-regulation
of IL-1ß and IGIF release during inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and TNF- were obtained from R&D Systems
(Minneapolis, MN).
N-acetyl-Tyr-Val-Ala-Asp-p-nitroanilide
(Ac-YVAD-pNA) and N-acetyl-Try-Val-Ala-Asp-aldehyde
(Ac-YVAD-cho) were obtained from Alexis (San Diego, CA). Active
recombinant human caspase-1 (rhcaspase-1) was generated with an
N-terminal polyhistadine tag in Escherichia coli and
purified by nickel-chelating Sepharose and size-exclusion
chromatography as described previously (16).
S-nitroso-N-acetyl-DL-penicillamine
(SNAP) was synthesized as described previously (17). Mouse RBCs were
prepared as described previously (18). A Th1-type T cell clone was
obtained from R. A. Hoffman (University of Pittsburgh). All other
chemicals were purchased from Sigma (St. Louis, MO) unless indicated
otherwise.
Isolation of mouse peritoneal M and cell culture
Murine peritoneal M were isolated from 6-wk-old iNOS KO
(iNOS-/-) and wild-type (wt) (iNOS+/+) mice
as described previously (19). Primary peritoneal M and the murine
M-like cell line RAW264.7 were cultured in DMEM containing 5%
low-endotoxin calf serum supplemented with 15 mM HEPES (pH 7.4), 2 mM
L-glutamine, 100 U/ml penicillin, and 100 µg/ml
streptomycin. Some cells were treated with LPS (2 µg/ml E.
coli 0111:B4; Sigma) and IFN- (10 U/ml) in the presence or
absence of 1.5 mM of
NG-monomethyl-L-arginine (NMA).
Cells in culture were used for various assays, including Northern blot,
Western blot, or caspase-1 activity, while media was obtained for
nitrite and cytokine analyses. Th1-type murine T cell lines (cloned and
provided by R. A. Hoffman) were maintained in culture with
irradiated murine spleen cells in Con A-conditioned media.
Measurement of cytokines, caspase-1 activity, and nitrite
The levels of TNF-, IFN-, and IL-1ß in cell culture
medium and in serum were measured by ELISA according to the
manufacturer’s protocols. In brief, culture media were removed from
the M cultures and centrifuged at 12,000 x g for 5
min; the supernatant was subjected to ELISA or nitrite analysis. For
assay of caspase-1 activity, the culture media were removed, and the
cells were washed with PBS and collected by plastic scrapper and
subsequently pelleted by centrifugation at 400 x g for
10 min at 4°C. The cell pellets were washed with ice-cold PBS and
resuspended in 100 mM of HEPES buffer (pH 7.4) containing protease
inhibitors (5 µg/ml aprotinin, 5 µg/ml pepstatin A, 10 µg/ml
leupeptin, and 0.5 mM PMSF). The cell suspension was lysed by three
freeze/thaw cycles, and the cytosolic fraction was obtained by
centrifugation at 12,000 x g for 20 min at 4°C.
Protein concentration was determined with the BCA protein assay
reagent (Pierce, Rockford, IL). Cytosol containing 200 µg of protein
was combined with 400 µM of the synthetic substrate Ac-YVAD-pNA in
150 µl of 100 mM HEPES (pH 7.4) containing 20% glycerol and protease
inhibitors, and the reaction was conducted for 1 h at 37°C.
Cytosolic caspase-1 activity was assayed by measuring the increased
absorbance at 405 nm (12). Nitrite accumulation in culture medium was
measured by the Griess reaction (17). rhcaspase-1 (8 µg) was treated
with various concentrations of SNAP on ice for 1 h. The enzyme was
then separated from the NO donor through a Sephadex G-25 column
preequilibriated with 100 mM of HEPES buffer (pH 7.4). rhcaspase-1 (200
ng) was used to measure the catalytic activity using the colorimetric
substrate Ac-YVAD-pNA (11).
In vitro cleavage of pro-IL-1ß and pro-IGIF
[35S]methionine-labeled murine pro-IL-1ß and pro-IGIF were synthesized using a TNT-coupled transcription and translation system (Promega, Madison, WI) (12). Aliquots (4 µl) of in vitro-translated, 35S-labeled proteins were incubated with rhcaspase-1 (8 ng), which was pretreated with or without 400 µM of SNAP in 10 µl of the total reaction volume in the presence or absence of 20 mM of DTT at 37°C for 1 h. The cleavage reaction was stopped by mixing with an equal volume of 2x SDS sample buffer and heating the mixture for 2 min. Cleavage profiles of pro-IL-1ß and pro-IGIF were examined by electrophoresis on 15% SDS-PAGE and protein visualized by fluorography.
Northern and Western blot analysis
Total RNA was isolated from RAW264.7 cells with RNAzol B (17).
Aliquots (20 µg) of RNA underwent electrophoresis on a 1% agarose
gel and were blotted to GeneScreen (Dupont New England Nuclear, Boston
MA). Membranes were hybridized to cDNA probes for murine iNOS,
TNF-, or IL-1ß. Relative levels of 18S rRNA were measured using an
18S-specific probe to assess RNA loading. For Western blot analysis,
the cytosolic extracts from M were obtained by three freeze/thaw
cycles and by centrifugation at 12,000 x g for 20 min
at 4°C. Cytosolic proteins (45 µg) were mixed with an equal volume
of 2x SDS-reducing sample buffer and boiled for 2 min. Samples were
separated on a 12% SDS-PAGE. Proteins were transferred onto a
nitrocellulose membrane, and the membrane was blotted by 5% nonfat
milk in PBS containing 0.01% Tween 20 (PBS-Tween) for 1 h at room
temperature and hybridized with anti-IL-1ß Ab (R&D Systems).
After three washes with PBS-Tween, the blot was hybridized with goat
anti-mouse IgG linked to horseradish peroxidase. The membrane was
developed with chemiluminescence reagent (DuPont New England Nuclear)
and exposed to Kodak X-Omat film to visualize the protein bands
(12). The intensity of the protein bands was measured with a Bio-Rad
densitometer (Hercules, CA).
Maturation of pro-IGIF in caspase-1-transfected cells
COS cells (3.5 x 105 cells per 35-mm dish)
were transfected with expression plasmids for murine pro-IGIF (3 µg)
and/or human ICE (3 µg) (20) using lipofectamine as described
previously (7). Cells were cultured with or without SNAP, Ac-YVAD-cho,
or SNAP and RBCs for 24 h. Culture media were collected and
centrifuged at 12,000 x g for 20 min at 4°C. After
serial dilution, the supernatants were incubated with nonadherent
Th1-type murine T cell lines (1.4 x 105 cells/150
µl/well of 96-well plates) for 18 h. IFN--producing activity
was assessed by measuring IFN- production in T cells by
ELISA.
In vivo production of IFN- and IL-1ß
iNOS KO and wt mice were injected i.p. with 10 mg/kg LPS. Some
mice received aminoguanidine (0.7 mmol/kg/injection) at 0 and 5 h
following LPS injection. Blood was collected via heart puncture at
10 h following LPS injection, and serum was obtained by
centrifugation at 12,000 x g for 10 min at
4°C. IFN- and IL-1ß levels were measured by ELISA.
Statistical analysis
Experiments were typically repeated a minimum of three times; data in the figures depict the results from either a representative experiment or combined data from all experiments as indicated in the figure legends. Data are presented as mean ± SD except for the Northern and Western blots. Significance was determined by the Student t test using the StatView statistics program (Abacus Concepts, Berkeley CA). Statistical significance was established at a p value of <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We hypothesized that induced NO would inhibit the release of
IL-1ß from activated M by direct inhibition of the proteolytic
activity of caspase-1. First, we characterized the time course for iNOS
and IL-1ß expression by LPS plus IFN--stimulated RAW264.7 cells in
the presence and absence of the NOS inhibitor NMA (Fig. 1
A). TNF- release, which
should not be suppressed by NO, was also measured. iNOS, IL-1ß, and
TNF- mRNA, which were not detectable before stimulation, were easily
detected by Northern blot analysis at 6 h poststimulation. iNOS
and IL-1ß mRNA levels remained elevated to the 24 h timepoint,
while TNF- mRNA levels had returned to baseline. Inclusion of NMA
resulted in higher mRNA levels for all three induced genes at 12 h
and beyond. Accumulation in the media of nitrite, a product of NO
metabolism, increased from 6 to 24 h following stimulation (Fig. 1B). This increase was suppressed by NMA. IL-1ß levels in
the media began to increase at 9 h, with a much greater elevation
in the NMA-treated cultures (Fig. 1C). In contrast, TNF-
levels were increased already by 3 h, with additional increases to
12 h (Fig. 1B); the addition of NMA resulted in only a
small increase in TNF- levels. The addition of NMA in the absence of
LPS plus IFN- stimulation did not stimulate IL-1ß release (data
not shown). Similar effects of NMA on NO production and IL-1ß
release, but not on TNF- production, were observed in RAW264.7 cells
treated with LPS alone (data not shown). Figure 2, A and B shows a
similar NO-dependent suppression of IL-1ß accumulation using
peritoneal M from either iNOS KO mice or their wt counterparts. As
expected, stimulation of M for 18 h with LPS plus IFN-
resulted in nitrite release from iNOS+/+ cells but not from
iNOS-/- cells. iNOS-/- cells released more
IL-1ß than did iNOS+/+ cells upon stimulation; however,
this release was not statistically significant
(p = 0.065). More importantly, the addition of
NMA increased IL-1ß accumulation in the culture medium of
iNOS+/+ cells but had no effect on IL-1ß release from
iNOS-/- M. Western blot analysis for IL-1ß was
performed on lysates from the peritoneal M. iNOS-/-
cells had lower levels of pro-IL-1ß than iNOS+/+ M
following stimulation along with detectable levels of processed IL-1ß
(Fig. 2C). NMA reduced the intracellular level of
pro-IL-1ß in iNOS+/+ cells but not in
iNOS-/- cells. Taken together, these data indicate that
induced NO prevents the processing of pro-IL-1ß and IL-1ß release
without suppressing mRNA levels.
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If NO prevents cytokine release by inhibition of
caspase-1, then exposure to NO should mimic the effect of a known
caspase-1 inhibitor. As shown in Figure 3A, the addition of the NO
donor SNAP to RAW264.7 cells stimulated with LPS plus IFN- in the
presence of NMA almost completely blocked IL-1ß release. This dose of
SNAP (200 µM) did not reduce cell viability during the 18 h time
course of this study (data not shown). A similar inhibition was seen
when the caspase-1 inhibitor Ac-YVAD-cho was used. NO is known to
stimulate cyclic GMP (cGMP) synthesis in cells (21); however,
the addition of the cell membrane-permeable analogue
8-bromo-cGMP did not reverse the enhanced release of IL-1ß
seen in the presence of NMA (Fig. 3A).
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release after 18 h. Cells transfected
with both pro-IGIF and caspase-1 released active IGIF (Fig. 3
B). The release of IGIF was suppressed if the COS cells
were incubated with Ac-YVAD-cho or SNAP. RBCs, which scavenge NO,
prevented the SNAP-induced suppression. Thus, NO mimics the effect of a
caspase-1 inhibitor. iNOS expression inhibits caspase-1 activity in RAW264.7 cells
Caspase-1 activity was monitored in cell lysates from RAW264.7
cells exposed to LPS plus IFN-. Compared with unstimulated controls,
caspase-1 activity increased slightly at 9 h poststimulation (Fig. 4A). The addition of NMA,
however, resulted in a marked increase in activity between 9 and
12 h that persisted to 24 h. Recent studies (11, 12, 13) have
shown that NO inhibits caspase activity by S-nitrosylation.
S-nitrosylated caspases can be reactivated in the presence
of the reducing agent DTT (12). When lysates from LPS plus
IFN--treated RAW264.7 cells were incubated with DTT for 20 min,
caspase-1 activity increased by 
68% (Fig. 4B). Lysates
from RAW264.7 cells stimulated with LPS plus IFN- in the presence of
NMA exhibited higher levels of caspase-1 activity, and this activity
was not increased further by treatment with DTT. Therefore, NO
suppresses caspase-1 activity in cells, at least in part, by a
mechanism consistent with S-nitrosylation.
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To determine whether NO would directly inhibit caspase-1 activity,
rhcaspase-1, prepared as described previously (16), was incubated with
various concentrations of SNAP for 1 h; activity was measured by a
colorimetric assay. Caspase-1 activity was inhibited by NO generated
from SNAP in a concentration-dependent manner (Fig. 5A). If the SNAP-treated
caspase-1 was subsequently exposed to 20 mM of DTT, the inhibition was
reversed. SNAP (400 µM) also prevented the proteolytic cleavage of
purified pro-IL-1ß (Fig. 5B) and pro-IGIF (Fig. 5C) by caspase-1. Cytokine maturation was also inhibited by
Ac-YVAD-cho and the thiol-modifying agents HgCl2 and
N-ethylmaleimide. DTT reversed the inhibition seen
with SNAP and HgCl2, which is consistent with reversible
modification of the reactive site thiol by NO and HgCl2.
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release in vivo
Experiments were conducted to determine whether iNOS expression
regulated cytokine release in vivo. IL-1ß and IFN- levels were
measured at 10 h after an i.p. LPS injection in wt
(iNOS+/+) and KO (iNOS-/-) mice. This
timepoint was chosen because iNOS expression peaks in several tissues
in rodents between 8 and 12 h in vivo following LPS injection
(22). KO mice exhibited 6- to 10-fold higher levels of both cytokines
(Figs. 6, A and B)
compared with wt mice at this timepoint. Administration of the iNOS
inhibitor aminoguanidine with the LPS resulted in higher IL-1ß and
IFN- levels in wt mice but not in iNOS-deficient animals.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, or both can
up-regulate iNOS expression in a wide range of cell types, including
M (23, 24). Therefore, an added consequence of the decrease in
IL-1ß and IFN- levels may be a decrease in the signals needed for
further iNOS expression.
The essential role of caspase-1 in cytokine processing was demonstrated
in caspase-1 KO mice (9). Otherwise overtly normal, these mice had much
lower IL-1ß, IL-1, and IFN- levels in response to LPS than
their wt counterparts. The reductions in IL-1ß levels were most
likely due directly to impaired processing of these cytokines, while
the inhibition of IFN- release could be accounted for by the failure
of these animals to release mature IGIF. Caspase-1, like the other
members of the caspase family, is produced in cells as an inactive
zymogen that must be proteolytically cleaved to form the active
protease (25). Endogenous regulators of caspase-1 activation have not
been identified, but it is presumed that other caspases, or even
caspase-1 itself, may serve this function. The pox virus protein CrmA
(26) and the baculovirus product p35 (20) both inhibit caspase-1
activity and consequently may serve to suppress cytokine processing as
a mechanism to suppress immune responses. Our results identify NO as
the first endogenous regulator of caspase-1 activity. By suppressing
caspase-1 activity, NO may act to down-regulate inflammatory responses
and prevent tissue damage. Under certain circumstances, induced NO may
exert direct tissue damage (27) or even promote other inflammatory
pathways (28). Both IL-1ß (29) and IFN- (30) participate in the
up-regulation of iNOS in several cell types. Therefore, down-regulation
of these cytokines might represent a feedback mechanism to inhibit
further iNOS expression. It is interesting to note that the expression
of iNOS parallels the release of IL-1ß and the increases in caspase-1
activity in our in vitro experiments. In fact, the large increases in
caspase-1 activity in the presence of NOS inhibition (Fig. 4) occur at
the timepoint (9 h) of maximal NO production, raising the
possibility that one function of induced NO is to regulate caspase
activity. We have shown that NO inhibits total protein synthesis in
RAW264.7 cells through the phosphorylation of eukaryotic initiation
factor-2 (31), raising the possibility that induced NO could
also inhibit caspase-1 production. Lower levels of pro-caspase-1
protein could account for the failure of DTT treatment to increase
caspase-1 activity in iNOS-expressing cells to levels seen in cells
stimulated with LPS plus IFN- in the presence of NMA (Fig. 4B).
The failure of DTT treatment to recover caspase-1 activity completely
in M lysates raises the possibility that NO may also suppress
caspase-1 activation. We found a similar response for caspase-3-like
activity in hepatocytes stimulated to undergo apoptosis, in which NO
not only suppressed caspase activity by S-nitrosylation but
prevented increases in caspase-3-like activity and presumably
activation by a cGMP-dependent mechanism (12). The addition of
8-bromo-cGMP did not suppress cytokine release in RAW264.7 cells,
suggesting that a similar mechanism does not apply to caspase-1.
Further studies are required to determine whether proteolytic
activation of caspase-1 is influenced by NO or whether NO suppresses
pro-caspase-1 protein levels as suggested above.
NOS inhibition did not influence TNF- release, which is consistent
with the notion that the effect of NO on cytokine processing is
specific for IL-1ß and IGIF. This outcome is not surprising, since
TNF- release does not require caspase-1 for maturation but instead
requires TNF- convertase, a metalloprotease that should not be
susceptible to NO inhibition (32). Furthermore, maximal TNF- release
occurs before the peak in NO production. NOS inhibition did result in
higher steady-state mRNA levels for TNF-, IL-1ß, and even
iNOS itself at 12 h and beyond, suggesting that NO has influences
on either transcription rates or mRNA degradation. The uniformity of
this response suggests a nonspecific mechanism and, again, may even
relate to suppression of total protein synthesis by NO. The specificity
for the down-regulation of cytokine processing by NO seems to lie in
the susceptibility of caspase-1 to S-nitrosylation by NO.
Both NO and other thiol-modifying agents completely inhibited
caspase-1-mediated cleavage of pro-IL-1ß and pro-IGIF. The reversal
of the NO-mediated inhibition by DTT is consistent with
S-nitrosylation as a mechanism, as described both for other
caspases (11, 12) and for other S-nitrosylated proteins (33, 34). It is unlikely that NO itself S-nitrosylates caspase-1;
rather, it is more likely that a reaction product with NO+
activity carries out this chemistry. Candidates include
N2O3, the reaction product of
NO+O2 (35), or even peroxynitrite (formed from
NO+O2-) (36) in the presence of transition metals
(37).
These results provide yet another role for induced NO in the direct
regulation of the inflammatory response. In addition to our
observations that induced NO can inhibit cytokine release, others have
shown that iNOS inhibits neutrophil accumulation in endotoxemia (38).
These observations are contrasted by findings in which induced NO
clearly participates in proinflammatory signaling. We have shown that
iNOS expression participates heavily in the activation of the
transcriptional factors NF-
B and STAT3 as well as in the expression
of IL-6 and granulocyte CSF in resuscitated hemorrhagic shock
(39). Others have shown that iNOS expression is required for the
up-regulation of the cytokines during Leishmania infection
(40). Although iNOS expression has typically been viewed as a direct
effector of tissue damage, it is now clear that induced NO also
modulates specific inflammatory signaling pathways. Understanding which
factors dictate a pro- vs antiinflammatory function for iNOS represents
an important area for continued investigation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Timothy R. Billiar, A1010 Presbyterian University Hospital, 200 Lothrop Street, Pittsburgh, PA 15213.
3 Abbreviations used in this paper: ICE, IL-1ß-converting enzyme; IGIF, IFN--inducing factor; M, macrophage(s); NO, nitric oxide; NOS, NO synthase; iNOS, inducible NOS; KO, knockout; rhcaspase, recombinant human caspase; SNAP, S-nitroso-N-acetyl-DL-penicillamine; wt, wild-type; NMA, NG-monomethyl-L-arginine; cGMP, cyclic GMP.
Received for publication February 17, 1998. Accepted for publication June 8, 1998.
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 M. A. Johnson, T. L. Macdonald, J. B. Mannick, M. R. Conaway, and B. Gaston Accelerated S-Nitrosothiol Breakdown by Amyotrophic Lateral Sclerosis Mutant Copper,Zinc-Superoxide Dismutase J. Biol. Chem., October 19, 2001; 276(43): 39872 - 39878. [Abstract] [Full Text] [PDF]
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H. Shimomura, M. Matsuura, S. Saito, Y. Hirai, Y. Isshiki, and K. Kawahara Lipopolysaccharide of Burkholderia cepacia and Its Unique Character To Stimulate Murine Macrophages with Relative Lack of Interleukin-1{beta}-Inducing Ability Infect. Immun., June 1, 2001; 69(6): 3663 - 3669. [Abstract] [Full Text] [PDF]
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G. Cai, R. Kastelein, and C. A. Hunter Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii Infect. Immun., December 1, 2000; 68(12): 6932 - 6938. [Abstract] [Full Text] [PDF]
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S. Fiorucci, L. Santucci, G. Cirino, A. Mencarelli, L. Familiari, P. D. Soldato, and A. Morelli IL-1{beta} Converting Enzyme Is a Target for Nitric Oxide-Releasing Aspirin: New Insights in the Antiinflammatory Mechanism of Nitric Oxide-Releasing Nonsteroidal Antiinflammatory Drugs J. Immunol., November 1, 2000; 165(9): 5245 - 5254. [Abstract] [Full Text] [PDF]
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 V. Jesenberger, K. J. Procyk, J. Yuan, S. Reipert, and M. Baccarini Salmonella-Induced Caspase-2 Activation in Macrophages: A Novel Mechanism in Pathogen-Mediated Apoptosis J. Exp. Med., October 2, 2000; 192(7): 1035 - 1046. [Abstract] [Full Text] [PDF]
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 C K Wong, C. Y Ho, E. Li, and C. Lam Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus Lupus, October 1, 2000; 9(8): 589 - 593. [Abstract] [PDF]
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X. Zhou, S. A. Gordon, Y.-M. Kim, R. A. Hoffman, Y. Chen, X.-R. Zhang, R. L. Simmons, and H. R. Ford Nitric Oxide Induces Thymocyte Apoptosis Via a Caspase-1-Dependent Mechanism J. Immunol., August 1, 2000; 165(3): 1252 - 1258. [Abstract] [Full Text] [PDF]
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 A. E. Karlsen, D. Pavlovic, K. Nielsen, J. Jensen, H. U. Andersen, F. Pociot, T. Mandrup-Poulsen, D. L. Eizirik, and J. Nerup Interferon-{gamma} Induces Interleukin-1 Converting Enzyme Expression in Pancreatic Islets by an Interferon Regulatory Factor-1-Dependent Mechanism J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 830 - 836. [Abstract] [Full Text]
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 J. S. Beckman Parsing the Effects of Nitric Oxide, S-Nitrosothiols, and Peroxynitrite on Inducible Nitric Oxide Synthase-Dependent Cardiac Myocyte Apoptosis Circ. Res., October 29, 1999; 85(9): 870 - 871. [Full Text] [PDF]
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 R. A. Schroeder, C. Cai, and P. C. Kuo Endotoxin-mediated nitric oxide synthesis inhibits IL-1beta gene transcription in ANA-1 murine macrophages Am J Physiol Cell Physiol, September 1, 1999; 277(3): C523 - C530. [Abstract] [Full Text] [PDF]
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Y.-M. Kim, C. A. Bombeck, and T. R. Billiar Nitric Oxide as a Bifunctional Regulator of Apoptosis Circ. Res., February 19, 1999; 84(3): 253 - 256. [Full Text] [PDF]
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 S. Fiorucci, A. Mencarelli, B. Palazzetti, P. Del Soldato, A. Morelli, and L. J. Ignarro An NO derivative of ursodeoxycholic acid protects against Fas-mediated liver injury by inhibiting caspase activity PNAS, February 27, 2001; 98(5): 2652 - 2657. [Abstract] [Full Text] [PDF]
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