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Department of Surgery, Toronto Hospital, and University of Toronto, Toronto, Ontario, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation and by inhibiting protein
synthesis. Since an antisense oligonucleotide for IL-1ß, a blocking
Ab to IL-1ß, and preincubation with the IL-1R antagonist all prevent
the delay in apoptosis, we conclude that IL-1ß acts in an autocrine
manner to inhibit granulocyte programmed cell death. We conclude that
caspase-1 (ICE) subserves both pro- and antiapoptotic roles; the latter
role is evident during inflammation as an inhibition of spontaneous
neutrophil apoptosis through the processing of IL-1ß. The
ICE-dependent activation of IL-1ß may represent a common autocrine
pathway for the divergent stimuli that inhibit the constitutive
expression of neutrophil programmed cell death during inflammation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Caspase-1, however, also processes pro-IL-1ß to yield active IL-1ß (4), a cytokine which plays a pivotal role in inflammatory cell activation (5) and is known to inhibit the expression of apoptosis (6). Thus, ICE may have divergent effects on cell survival, depending upon which of its substrates is preferentially processed.
Apoptosis in the mature polymorphonuclear neutrophil is a constitutive process that results in a rapid turnover of the circulating neutrophil population with a t1/2 of 5 to 6 h in vivo (7) and 24 to 36 h in vitro (7, 8). However, the expression of neutrophil apoptosis can be regulated by inflammatory mediators. It can be accelerated by IL-6 (9), TNF (10), IL-10 (11), and by the ingestion of Escherichia coli (8). Conversely, it is inhibited by such bacterial products as LPS and FMLP (7), by proinflammatory cytokines such as granulocyte-macrophage (GM)-CSF, granulocyte CSF (12), and IL-1ß (13), and by the engagement of cell surface ß2 integrins (14). Some stimuli, in particular TNF and IL-6, have been variously reported to accelerate or delay apoptosis, depending upon the experimental circumstances and the cells studied. The mechanism through which these divergent inflammatory mediators delay neutrophil apoptosis is unknown. The Bcl-2 family of antiapoptotic proteins is not expressed in quiescent mature neutrophils (15) nor is it expressed in cells in which apoptosis has been inhibited by LPS or GM-CSF (16). However both LPS and GM-CSF are known to induce the neutrophil synthesis of IL-1ß, which itself decreases spontaneous neutrophil apoptosis (17).
Therefore, we evaluated the expression and activities of IL-1ß and caspase-1 in neutrophils that had been activated by a bacterial product, LPS, and a host-derived cytokine, GM-CSF, both of which are known inhibitors of neutrophil apoptosis. Here, we show that these two activational stimuli up-regulate the expression of both caspase-1 and its substrate, pro-IL-1ß, and also that newly synthesized IL-1ß inhibits the expression of the constitutive neutrophil cell death program. These results demonstrate that the prototypical proapoptotic enzyme, caspase-1, can inhibit the expression of neutrophil apoptosis. In addition, they establish a role for neutrophil IL-1ß as an autocrine regulator of cell survival during acute inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DMEM, penicillin/streptomycin solution, L-glutamine, PBS, and FCS were purchased from Life Technologies (Burlington, Ontario, Canada). YVAD-CMK, an irreversible inhibitor of caspase-1, was purchased from Calbiochem (San Diego, CA). Dihydrorhodamine 123 was purchased from Molecular Probes (Eugene, OR). All other chemicals were supplied by Sigma (St. Louis, MO) unless otherwise stated. A phosphorothioate-modified antisense oligonucleotide to IL-1ß was purchased from Life Technologies. rIL-1R antagonist (rIL-1RA) was a gift of Amgen (Boulder, CO).
Antibodies
Polyclonal antiphosphotyrosine Ab and horseradish peroxidase-conjugated anti-rabbit Ig were purchased from Serotec (Hornby, Ontario, Canada). A blocking mAb to IL-1ß was supplied by Genzyme (Cambridge, MA).
Probes
cDNA for human caspase-1 was kindly donated by Immunex (Seattle, WA). IL-1ß cDNA was supplied by the American Type Culture Collection (Manassas, VA).
Neutrophil isolation
Neutrophils were isolated from healthy volunteers by dextran sedimentation and centrifugation through a discontinuous Ficoll gradient (8). Isolated neutrophils were resuspended in polypropylene tubes at a concentration of 1 x 106 cells/ml in DMEM supplemented with 10% FCS, 1% glutamine, and 1% penicillin/streptomycin solution. Neutrophil purity as assessed by size and granularity on flow cytometry was consistently >95%.
Quantification of apoptosis
Neutrophil apoptosis was quantified by flow cytometry as the percent of cells with hypodiploid DNA (18). Cells were centrifuged at 200 x g for 10 min, gently resuspended in 500 µl of hypotonic fluorochrome solution (50 µg/ml propidium iodide, 3.4 mM sodium citrate, 1 mM Tris, 0.1 mM EDTA, and 0.1% Triton X-100), and stored in the dark at 4°C for 3 to 4 h before analysis using a Coulter Epics XL-MCL cytofluorometer (Hialeah, FL). A minimum of 5000 events were collected and analyzed. Apoptotic nuclei were distinguished from normal neutrophil nuclei by their hypodiploid DNA; neutrophil debris was excluded from analysis by raising the forward threshold. Apoptosis was assessed at 24 h after experimental manipulations unless otherwise stated.
Electrophoretic mobility shift assay
Nuclear extracts were prepared from 20 x
106 isolated neutrophils (19). A total of 5 µg of
protein from the extracts was preincubated with the nonspecific DNA
competitor poly(dI-dC) (5 mg) for 10 min at room temperature. A
[32P]-radiolabeled probe that contained two NF-B sites
and was derived from the HIV-1 enhancer was added for an additional 20
min at room temperature. DNA/protein complexes were resolved on a 5%
nondenaturing polyacrylamide (60:1 cross-link)/Tris glycine gel, and
autoradiographs were prepared by exposure at -70°C using Kodak
X-OMAT film. To demonstrate the specificity of the protein/DNA complex,
either a 125 M excess of the unlabeled probe or a mutated HIV enhancer
probe was added to the nuclear extract before the addition of the
radiolabeled probe (19). The sequence of the plus strand of the
oligonucleotide used was as follows: HIV-1 enhancer 5'-AGG GAC TTT CCG
CTG GGA CTT TCC-3'.
Inhibition of IL-1ß translation using an antisense oligodeoxynucleotide
Neutrophils (1 x 105) were preincubated with 5 µM of a phosphorothioate-modified (20) oligodeoxynucleotide antisense probe to IL-1ß mRNA (5'-CTC AGG TAC TTC TGC CAT-3'), which was complementary to six bases starting at the translation initiation codon, ATC (21), or were preincubated with a sense probe as a control for 6 h; the neutrophils were then incubated with LPS (1 µg/ml) or GM-CSF (100 U/ml).
Northern blot analysis
Total RNA was extracted using the guanidinium-isothiocyanate
method. Briefly, 50 x 106 neutrophils were lysed
in a 4 M guanidinium-isothiocyanate solution containing 25 mM sodium
citrate, 0.5% sarcosyl, and 100 mM ß-mercaptoethanol. RNA was
denatured, electrophoresed through a 1.3% formaldehyde-agarose gel,
and transferred to nylon membrane. Hybridization was performed at
42°C for 18 h with an [
-32P]dCTP-labeled,
random-primed cDNA probe for either human ICE or IL-1ß cDNA.
Membranes were stripped and hybridized to an 18S ribosomal subunit cDNA
probe to correct for variability in gel loading. mRNA expression was
quantified using a PhosphorImager with accompanying ImageQuant software
(Molecular Dynamics, Sunnyvale, CA).
IL-1ß ELISA
Supernatants were collected at the times indicated and stored at -80°C. Concentrations of mature IL-1ß in the medium were measured by ELISA using a commercially available assay (Genzyme).
Assay of caspase-1 activity
Cell lysates were prepared from the membrane fraction of 20 x 106 neutrophils following experimental manipulation. Aliquots of the lysates (10 µl) were diluted in assay buffer (100 mM HEPES (pH 7.5), 10% sucrose, and 0.1% 3-([3-cholamidopropyl]dimethylammonio)-1-propanesulfonate) containing 20 µM Ac-Tyr-Val-Ala-Asp-7-amino-4-methylcoumarin (Calbiochem, Hornby, Ontario, Canada) and then incubated for 45 min at room temperature. The release of 7-amino-4-methylcoumarin was detected by continuous measurement using a Perkin-Elmer LS50 luminescence spectrometer (London, England) with an excitation of 380 nm and an emission slit at 460 nm. Specific ICE (caspase-1) activity is measured as pmol/s per milligram of protein.
Statistical analysis
Individual experiments were repeated a minimum of four times;
results are expressed as the mean ± SD. Analysis was performed
using the Student t test or ANOVA with Scheffe’s
correction. The level for statistical significance was set at
p < 0.05.
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Results |
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Preincubating resting neutrophils with either LPS or GM-CSF
resulted in a significant inhibition of the constitutively expressed
cell death program. The antiapoptotic effects of both could be blocked
either by tyrosine kinase inhibition with herbimycin A or by the
inhibition of NF-B activation with pyrrolidine dithiocarbamate
(PDTC) (Fig. 1
A).
Inhibiting protein synthesis with cycloheximide (CHX) blocked the
apoptotic delay resulting from exposure to LPS or GM-CSF (Fig. 1A). Both herbimycin and PDTC inhibited NF-B
activation in response to LPS (Fig. 1B), suggesting
that tyrosine phosphorylation is an upstream event to NF-B
activation in the cascade which leads to the inhibition of the
LPS-induced apoptotic delay. CHX itself had no effect on NF-B
activation (Fig. 1C). Similar results were obtained
for GM-CSF (data not shown). Taken together, these results suggested
that delayed apoptosis in LPS- or GM-CSF-treated neutrophils was
mediated by an inducible protein or proteins whose expression was
signaled through a tyrosine kinase-dependent pathway and was dependent
on activation of the transcription factor, NF-B.
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Neutrophils exposed to either LPS or GM-CSF released IL-1ß into
the culture medium, an effect that could be inhibited by herbimycin A,
PDTC, and CHX (Fig. 2). IL-1ß is
synthesized and released as a 31-kDa precursor that is activated
through cleavage at an aspartic acid residue by ICE (13). Exposing
resting neutrophils to LPS (Fig. 3A) or GM-CSF (Fig. 3B) induced significant increases in the expression
of mRNA for pro-IL-1ß, an effect that could be reduced by tyrosine
kinase inhibition with herbimycin and by the inhibition of NF-B
activation with PDTC (Fig. 3A).
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ICE message was expressed at low levels in resting neutrophils,
despite the fact that 
35% of these cells showed flow cytometric
evidence of apoptosis after 18 h in culture (Fig. 1
A). Both LPS (Fig. 3A) and GM-CSF
(Fig. 3B) up-regulated message for ICE, although the
functional consequence was the inhibition of spontaneous neutrophil
apoptosis (Fig. 1A). The increased expression of ICE
mRNA was associated with an increase in specific ICE activity (Fig. 3C) but was not associated with an increase in
caspase 3 (CPP32) proteolytic activity (data not shown).
Increased ICE-dependent IL-1ß processing prevents the activation-induced apoptotic delay
Inhibiting ICE activity with the irreversible tetrapeptide
inhibitor YVAD-CMK, largely prevented the LPS- or GM-CSF-induced
release of IL-1ß (Fig. 4A) and blocked the
corresponding apoptotic delay (Fig. 4B). Three
separate strategies were used to confirm the necessary role of newly
processed IL-1ß in the observed apoptotic delay. Preincubating
neutrophils with a phosphorothioate-modified antisense
oligodeoxynucleotide to IL-1ß mRNA (21) blocked the LPS- or
GM-CSF-stimulated increases in IL-1ß release (Fig. 5A) and prevented the
apoptotic delay associated with exposure to these stimuli (Fig. 5B). The addition of rIL-1ß to cells treated with
the antisense probe restored the apoptotic delay (Fig. 5C). Similarly, adding a specific blocking mAb to
IL-1ß also inhibited the antiapoptotic effects of LPS, GM-CSF, and
rIL-1ß (Fig. 6). Finally, preincubating
neutrophils with human rIL-1RA restored the rates of apoptosis to near
normal levels following exposure to LPS or GM-CSF, although this effect
could be overcome by the addition of rIL-1ß (Fig. 7). An inhibition
of IL-1ß activation or cellular binding by any of the strategies
described above had no effect on the functional priming activities of
LPS or GM-CSF, and respiratory burst activity was normal (data not
shown).
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), IL-1ß synthesis (Fig. 5), or
IL-1ß binding (Figs. 6 and 7) to cells does not completely reverse
the delay, other autocrine factors may be involved. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After 24 h in culture, 30 to 40% of quiescent neutrophils
exhibit morphologic features of apoptosis, a consequence of the
execution of a constitutively expressed cell death program.
The expression of apoptosis is accelerated following the ligation of
cell surface Fas with its physiologic ligand, Fas ligand (22), or with
an agonistic anti-Fas Ab (23). In contrast, the constitutive
apoptotic program can be inhibited by a variety of signals that are
associated with the expression of an inflammatory response, including
exposure to bacterial LPS (7) or an array of proinflammatory cytokines
(12); the program can also be inhibited by the process of
transmigration into an inflammatory focus (14). As shown here, the
inhibition of apoptosis is an active process, dependent upon the
tyrosine phosphorylation of as yet unidentified intracellular proteins,
the activation of the nuclear transcription factor NF-B, and the
synthesis of new protein by the
neutrophil.
There is growing consensus that progression to apoptosis is the normal
default state for many cells, and that survival is contingent upon
the rescue of cells from programmed cell death by signals
from the environment. For the neutrophil, prolonged survival is
intimately linked to functional activation. Activational regulation of
the expression of neutrophil apoptosis has been suggested by previous
studies. Thus, the inhibitory effects of GM-CSF are mediated through
the tyrosine phosphorylation of lyn, and can be blocked by
inhibitors of tyrosine kinases (16). Moreover, neutrophil
activation by LPS is associated with a dissociation of
inhibitor-B and the release of NF-B; NF-B, in turn,
can render lymphocytes, fibroblasts, and macrophages refractory to the
proapoptotic effects of TNF (24, 25). Additionally, NF-B is known to
regulate the transcription of IL-1ß in U937 cells (26). Finally the
inhibitory effects of GM-CSF are known to be dependent upon new protein
synthesis, since they can be blocked by inhibitors of protein synthesis
(11). The results of the present study suggest that these regulatory
effects are mediated by ICE-dependent processing of pro-IL-1ß, and
establish a novel role for caspase-1 in the inhibition of the
expression of apoptosis under conditions of cellular activation.
Whether the ICE-dependent generation of IL-1ß represents a single
final common pathway for the multiple signals that inhibit the
constitutive cell death program of the neutrophil is unknown. The
surface receptors for LPS and GM-CSF are distinct. Moreover, LPS binds
to the neutrophil CD14R (27), leading to the activation of a p38
mitogen-activated protein kinase but not to the activation of
extracellular signal-related kinase (ERK)-1 (p42) or ERK-2 (p44) (28);
the ligation of CD14 with an agonistic Ab, RM052, triggers a comparable
apoptotic delay (our unpublished observations). The receptor for GM-CSF
comprises two chains, an - and a ß-chain (29). GM-CSF binding to
its receptor on the neutrophil appears to preferentially activate ERK-1
and ERK-2 (30). Both receptors are linked to intracellular signaling
cascades that are dependent upon tyrosine phosphorylation and the
activation of the transcription factor NF-B. Although the inhibition
of early events following receptor engagement (tyrosine kinase and
NF-B activation) or protein synthesis was able to completely block
the activation-induced apoptotic delay, interventions targeting ICE
(YVAD-CMK) or IL-1ß (antisense oligonucleotide, blocking Ab, or
IL-1RA) alone only partially inhibited this effect. Thus, we cannot
exclude the possibility that a second caspase and protein mediator is
implicated in the inhibition of the constitutive apoptotic program
during cellular activation.
Contrary to what has been observed in other cells, we found no evidence that ICE induces apoptosis in activated neutrophils. Thus the enzyme was expressed at lower levels in spontaneously apoptotic cells; both increased expression and activity, measured as cleavage of the tetrapeptide, YVAD, were associated with the inhibition rather than the activation of apoptosis. Moreover, even when the processing of pro-IL-1ß was blocked by the use of an antisense oligonucleotide, there was no observed shift in ICE activity to an enhanced expression of apoptosis. Whether this lack of proapoptotic activity reflects intrinsic alterations in the ICE molecule or altered activity in the inflammatory intracellular milieu of the neutrophil merits further investigation. The suppression of apoptosis by a truncated version of the ICE homologue, Ich-1, has previously been reported (31), and mice with a targeted deletion of the ICE gene demonstrate apparently normal development and normal expression of macrophage and thymocyte apoptosis (32). It is intuitively apparent that inhibiting the proapoptotic activity of ICE is a prerequisite for the ongoing generation of IL-1ß by a cell.
IL-1 is a pleiotropic cytokine that exerts multiple paracrine and endocrine influences on cellular homeostasis during acute inflammation (5). By virtue of its effects on neutrophil functional survival, it can also be considered an autocrine cell survival factor that promotes cellular longevity by inhibiting the expression of programmed cell death. Regulating its activity by the targeting of signaling cascades, gene transcription, or IL-1 binding to cell surface receptors provides a novel option for the regulation of inflammatory cell survival, and consequently for the therapy of a broad group of disease processes characterized by a dysregulated inflammatory response, from arthritis to inflammatory bowel disease to sepsis.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. John C. Marshall, Eaton North 9–234, Toronto Hospital, General Division, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. E-mail address:
3 Abbreviations used in this paper: ICE, IL-1ß-converting enzyme; GM-CSF, granulocyte-macrophage CSF; IL-1RA, IL-1R antagonist; CHX, cycloheximide; ERK, extracellular signal-related kinase; PDTC, pyrrolidine dithiocarbamate.
Received for publication January 8, 1998. Accepted for publication March 16, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B subunit genes modulates IB and interferon ß expression. Cell Growth Differ. 6:965.[Abstract]
B in preventing TNF--induced cell death. Science 274:782.-induced apoptosis by NF-B. Science 274:787.B regulates IL-1ß transcription through a consensus NF-B binding site and a nonconsensus CRE-like site. J. Immunol. 153:712.[Abstract]
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p < 0.05 vs
LPS. B, The electrophoretic mobility shift assay showed both
an activation of NF-
