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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-06-1778.
HEMATOPOIESIS
From Institut National de la Santé et de la
Recherche Médicale (INSERM) U517, Institut Fédératif
de Recherche (IFR) 100, Faculty of Medicine, Dijon, France; Centre
National de Recherches Scientifiques (CNRS) UMR 8603, IFR Necker,
Paris, France; and INSERM U362, Institut Gustave Roussy,
Villejuif, France.
Caspases are cysteine proteases involved in apoptosis and cytokine
maturation. In erythroblasts, keratinocytes, and lens epithelial cells
undergoing differentiation, enucleation has been regarded as a
caspase-mediated incomplete apoptotic process. Here, we show that
several caspases are activated in human peripheral blood monocytes
whose differentiation into macrophages is induced by macrophage colony-stimulating factor (M-CSF). This
activation is not associated with cell death and cannot be detected in
monocytes undergoing dendritic cell differentiation in the presence of
interleukin-4 (IL-4) and granulocyte-macrophage
colony-stimulating factor (GM-CSF). The mechanisms and
consequences of caspase activation were further studied in U937 human
monocytic cells undergoing phorbol ester-induced differentiation
into macrophages. Differentiation-associated caspase activation
involves the release of cytochrome c from the mitochondria and leads to
the cleavage of the protein acinus while the poly(ADP-ribose)polymerase remains uncleaved. Inhibition of caspases by either exposure to the
broad-spectrum inhibitor
benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (z-VAD-fmk) or expression of the p35 baculovirus inhibitory protein or
overexpression of Bcl-2 inhibits the differentiation process. In
addition, z-VAD-fmk amplifies the differentiation-associated production
of radical oxygen species in both phorbol ester-differentiated U937 cells and M-CSF-treated monocytes, shifting the
differentiation process to nonapoptotic cell death. Altogether, these
results indicate that caspase activation specifically contributes to
the differentiation of monocytes into macrophages, in the absence of
cell death.
(Blood. 2002;100:4446-4453) A family of cysteine proteases known as caspases
plays a central role in many forms of apoptosis.1 These
enzymes are synthesized as inactive zymogens that must be cleaved after
conserved aspartate residues to be activated. Two main pathways were
shown to trigger caspase activation in cells undergoing
apoptosis.2 Schematically, the intrinsic pathway involves
the disruption of the outer mitochondrial membrane barrier function,
thus permitting the release of proapoptotic molecules from the
mitochondria to the cytosol. One of these molecules is cytochrome c,
which, once in the cytosol, oligomerizes the adaptor molecule Apaf-1 to
recruit and activate the initiator caspase-9. In turn, caspase-9
cleaves and activates downstream effector enzymes such as caspase-3.
The extrinsic pathway to cell death involves plasma membrane death
receptors. In response to their engagement, these receptors trimerize
and recruit the adaptor molecule Fas-associated death domain protein
(FADD), which, in turn, interacts with and activates an
initiator enzyme, usually caspase-8. This enzyme, either directly or
through the previously described mitochondrial pathway, activates
downstream effector enzymes including caspase-3.3 In both
pathways, effector caspases trigger the limited proteolytic cleavage of
intracellular structural and regulatory proteins, thus leading to
membrane blebbing, chromatin condensation, and nuclear DNA
fragmentation, which characterize apoptosis.
Most of the studies concerning caspases have highlighted the
relationship between their activation and the occurrence of cell death
by apoptosis. However, caspase-1 was initially identified as the
protease responsible for the maturation of the multifunctional cytokine
interleukin-1 The present study identifies an activation of caspase-3 and caspase-9
in human peripheral blood monocytes induced to differentiate into
macrophages in response to macrophage colony-stimulating factor
(M-CSF). Caspase activation was not related to apoptosis; nor it was
observed in monocytes exposed to IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for inducing their
differentiation into dendritic cells. By using the U937 human monocytic
cell line exposed to phorbol ester as a model system, we show that
caspase activation actively contributes to the differentiation of
monocytes into macrophages.
Drugs and chemical reagents
Antibodies
Cell culture and differentiation Human peripheral blood monocytes were obtained from healthy donors with informed consent and purified using a monocyte isolation kit with a light-scattering (LS) column according to the manufacturer's instructions (Miltenyi Biotec, Paris, France) and then incubated (2.5 × 105/mL) with 100 ng/mL M-CSF or with a combination of GM-CSF (100 ng/mL), IL-4 (10 ng/mL), and/or -mercaptoethanol (50 µM) for up to 7 days.15
The human leukemic cell line U937 (CRL-1593.2, mycoplasma free and
virus free; American Type Culture Collection [ATCC], Rockville, MD)
and a derivative cell clone containing the full-length human
bcl-2 cDNA (U937/Bcl-2, kindly provided by J. Bréard, INSERM
U461, Chatenay-Malabry, France) were grown in suspension in RPMI 1640 medium with glutamax-I (Gibco, Life Technologies, Cergy
Pontoise, France) supplemented with 10% (vol/vol) fetal
bovine serum (BioWhittaker, Fontenay-sous-bois, France) in an
atmosphere of 95% air and 5% CO2 at 37°C. Cell
viability was determined by using a trypan blue exclusion assay. To
ensure exponential growth, cells were resuspended at a density of
0.5 × 106/mL in fresh medium 24 hours before each
treatment. To induce differentiation, cells were cultured in the
presence of 20 nM TPA for up to 72 hours. After treatment, adherent
cells were harvested using a cell scraper. Cellular differentiation was
assessed by May-Grünwald Giemsa staining and CD1a, CD11b, and
CD14 plasma membrane expression analysis as
described.16
Cell transfection The FLAG-peptide epitope tagged baculovirus p35 cDNA (kindly provided by J. C. Ameissen, INSERM EPI 99.22, Paris, France) was inserted in a pTarget vector (Promega, Charbonnière, France). Stable transfection was performed by electroporation of 1.0 × 106 U937 cells with 10 µg pTarget containing or not containing p35 cDNA, and selection was done by culturing the cells for 4 weeks in the presence of 1 mg/mL geneticin (G418) to generate mixed cell populations in which expression of p35 was detected by immunoblotting using an anti-FLAG antibody (Boehringer-Mannheim).DNA fragmentation analysis Cellular DNA was extracted by a previously described salting-out procedure,17 and electrophoresis was performed in 1.8% agarose gel in Tris (tris(hydroxymethyl)aminomethane)-borate-EDTA (ethylenediaminetetraacetic acid) buffer (pH 8.0) at 20 V for 14 hours. After electrophoresis, DNA was visualized by ethidium bromide staining.Western blot analysis Whole-cell lysates were prepared by lysing the cells in boiling buffer (1% SDS, 1 mM sodium vanadate, 10 mM Tris [pH 7.4]) in the presence of protease inhibitors (0.1 mM phenylmethylsulfonyl fluoride [PMSF], 2.5 µg/mL pepstatin, 10 µg/mL aprotinin, 5 µg/mL leupeptin). The viscosity of the samples was reduced by several passages through a 26-gauge needle. Mitochondrial (Mit) and cytosolic (S100) fractions for cytochrome c release studies were prepared as previously described.18 Protein concentration was measured using the Bio-Rad DC protein assay kit (Ivry sur Seine, France). Thirty microgram proteins were incubated in loading buffer (125 mM Tris-HCl [pH 6.8], 10%-mercaptoethanol, 4.6% SDS, 20% glycerol, and
0.003% bromophenol blue), separated by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and
electroblotted to polyvinylidene fluoride (PVDF) membrane
(Bio-Rad). After blocking nonspecific binding sites overnight by 5%
nonfat milk in TPBS (phosphate-buffered saline [PBS], Tween
20 0.1%), the membrane was incubated for 2 hours at room temperature
with the primary Ab. After 2 washes in TPBS, membrane was incubated
with horseradish peroxidase-conjugated goat antimouse or antirabbit
(Jackson ImmunoResearch Laboratories, West Grove, PA) or swine antigoat
(Caltag Laboratories, Burlingame, CA) Abs for 30 minutes at
room temperature and then washed twice in TPBS. Immunoblot was revealed
using enhanced chemiluminescence detection kit (Amersham, Les Ulis,
France) by autoradiography.
Caspase activity measurement Cells were incubated in lysing buffer (150 mM NaCl, 50 mM Tris-HCl [pH 8.0], 0.1% SDS, 1% Nonidet P-40 [NP-40], 0.5% sodium deoxycholate) for 30 minutes at 4°C and centrifuged (10 000g, 20 minutes, 4°C). Fifty microgram proteins of the resulting supernatant was incubated in buffer assay (100 mM HEPES [N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid] [pH 7.0], 1 mM ETDA, 0.1% CHAPS [3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfate], 10% glycerol, 20 mM dithiothreitol) in the presence of 100 µM fluorogenic peptide substrate (Ac-DEVD-AMC [7-amino-4-methylcoumarin], z-IETD-AFC [7-amino-4-triFluoro-methylcoumarin], z-VDVAD-AFC, and Ac-LEHD-AFC; France Biochem, Meudon, France). AMC and AFC released from the substrate were excited at 380 and 400 nm to measure emission at 460 and 505 nm, respectively. Fluorescence was monitored continuously at 37°C for 30 minutes in a dual luminescence fluorimeter (MicroTek OS; Bio-Tek Kontron Instruments, Winooski, VT). Enzyme activities were determined as initial velocities expressed as relative intensity per minute per milligram.Immunofluorescence studies Immunofluorescence analysis was performed as previously described.19 Briefly, cells were fixed in 2% paraformaldehyde (5 minutes, 4°C), washed twice, saturated in PBS, 0.1% saponin, 1% bovine serum albumin, and incubated for 2 hours at room temperature in the presence of primary antibody diluted in PBS, 0.1% saponin, and 0.5% bovine serum albumin. After washing, cells were incubated for 30 minutes with 488-alexa goat antirabbit Ab and/or 568-alexa goat antirabbit Ab (Molecular Probes, Eugene, OR). Nuclei were stained with Hoechst 33342 (Sigma-Aldrich). Analyses were made by using a fluorescence (Nikon, Champigny, France) or a confocal (Leica, Bron, France) microscope. The caspase-3 and -9 active fragments were also detected by flow cytometry using a Becton Dickinson FACScan cytometer (Le Pont de Claix, France).Flow cytometry analyses Mitochondrial membrane depolarization was analyzed using the DePsipher kit (R&D Systems) according to the manufacturer's instructions. Briefly, 106 cells were incubated for 20 minutes at 37°C in the presence of 5 µg/mL DePsipher solution and then washed twice in PBS. Dihydroethidine was used as a substrate for measuring radical oxygen species (hydrogen peroxide) production. Expression of phosphatidylserine in the external layer of the plasma membrane was determined by studying the fixation of annexin V-FITC in the presence of Ca++ in cells that remain nonpermeant to propidium iodide (TACS annexin V-FITC assay, R&D Systems). All these analyses were performed by the use of a FACScan cytometer (Becton Dickinson).
The differentiation of human peripheral blood monocytes into
macrophages is associated with caspase activation. Human monocytes were
purified from healthy donor peripheral blood and exposed to 100 ng/mL
M-CSF to trigger their differentiation into macrophages.15 Using a flow cytometry assay, we detected the appearance of caspase-3 active fragments in the cells 24 hours after the beginning of culture
in the presence of M-CSF (Figure 1A). The
appearance of these active fragments in the cytoplasm was not
associated with apoptotic features; for example, in the cells labeled
with the antiactive caspase-3 antibody, Hoechst-stained nuclear
chromatin did not demonstrate a characteristic apoptotic condensation
and the nucleus was not fragmented (Figure 1D). Interestingly, when human monocytes were induced to differentiate into dendritic cells by
exposure to 10 ng/mL IL-4 and 100 ng/mL GM-CSF, caspase-3 active fragments could not be identified (Figure 1B-D). Similar results were
obtained by using an anticaspase-9 active fragments antibody (Figure
1C-D). These results suggested that the differentiation of monocytes
into macrophages could specifically involve the activation of
several caspases.
Caspases are activated during TPA-induced U937 cell differentiation. To
confirm these observations, we used the U937 human monocytic cells.
Exposure of these cells to 20 nM 12-O-tetradecanoylphorbol 13-acetate (TPA) induces their differentiation into
macrophages.20,21 The differentiated phenotype includes
adhesion of these initially floating cells to the culture flask (Figure
2A) and increased expression of the
glycoprotein CD11b on their plasma membrane (Figure 2B). To investigate
whether caspases were activated during this differentiation process, we
first studied the ability of cell lysates to cleave DEVD-AMC, a
fluorigenic peptide that mimics the target site of caspase-3 and
closely related caspases. Acquisition of the differentiated phenotype
was associated with an increase in the DEVD-AMC cleavage activity that
appeared between 6 and 12 hours after the beginning of cell treatment,
reached a maximum between 12 and 24 hours, and then decreased with time
(Figure 2C). The ability of lysates from cells undergoing
differentiation to cleave 3 other caspase substrates, namely VDVAD-AFC
(caspase-2), LEDH-AFC (caspase-9), and IETD-AFC (caspase-8), was
observed to increase along the differentiation process with similar
kinetics (Figure 2C). Caspase-3 activation was further confirmed by
flow cytometry analysis using an antibody that specifically recognizes active caspase-3 fragments (Figure 2D). The mean fluorescence index
increased from 6.0 ± 1.1 at day 0 to 13.9 ± 4.3 at day 2 (mean
± SD of 3 experiments). Lastly, Western blotting identified the 21-, 19-, and 17-kDa cleavage fragments of the protein in U937 cells exposed
for 24 hours to 20 nM TPA (Figure 2E).
TPA-induced caspase activation is not associated with apoptosis. To
determine whether caspase activation was associated with apoptosis, we
performed immunofluorescence microscopic studies. The active fragments
of caspase-3 and caspase-9 were detected in the cytoplasm of U937 cells
exposed for 24 hours to TPA. In labeled cells, Hoechst 33342 staining
of the nuclear chromatin did not show the chromatin condensation or the
nuclear fragmentation observed in U937 cells undergoing typical
apoptosis under etoposide exposure (Figure
3A-B). A careful analysis of TPA-treated
cells demonstrating morphologic apoptotic features indicated that their percentage always remained lower than 4% (Figure 3C, upper numbers). Agarose gel electrophoresis of DNA did not detect oligonucleosomal DNA
fragmentation at any step of the differentiation process (Figure 3C),
Western blot analysis of the poly(ADP-ribose)polymerase (PARP) nuclear
enzyme did not identify any cleavage of the 116-kDa parental protein in
an 85-kDa (amino-terminal) fragment (Figure 3C), and cells remained
unlabeled with annexin V (Figure 3D) while these 3 events were
associated with etoposide-induced U937 cell apoptosis (Figure 3C-D).
However, both etoposide-induced apoptosis and TPA-mediated differentiation were associated with the appearance of the 23-kDa active fragment of the protein acinus, a caspase-3-mediated cleavage product of the 98-kDa mature protein (Figure 3C).22
Differentiation-associated caspase activation involves the
mitochondria. In a search for the molecular pathway leading to caspase
activation during TPA-induced U937 cell differentiation, we first
investigated the role of the mitochondria.23 Exposure of
U937 cells to TPA induced a slight decrease in
Overexpression of Bcl-2, expression of the baculovirus p35, and
z-VAD-fmk treatment prevent both caspase activation and TPA-induced U937 cell differentiation. Overexpression of Bcl-2 decreased the percentage of U937 cells that became adherent to the culture flask (Figure 5A) as well as the number of
those who expressed CD11b (Figure 5B) in response to TPA exposure.
Similarly, expression of the baculovirus caspase inhibitory protein
p3525 in U937 cells prevented TPA-induced DEVDase activity
(Figure 6A), cell adhesion to the culture
flasks (Figure 6B), and CD11b expression increase (Figure 6C). Lastly,
the broad-spectrum caspase inhibitor z-VAD-fmk26
completely suppressed DEVD-AMC peptide cleavage activity (Figure 6D) as
well as other caspase activities (not shown) and the appearance of the
23-kDa acinus fragment (not shown) in TPA-treated U937 cells. The
z-VAD-fmk prevented the adhesion of TPA-treated U937 cells in a
dose-dependent manner (Figure 6E) and blocked the appearance of CD11b
on their plasma membrane (Figure 6F).
The caspase inhibitor z-VAD-fmk induces a switch from differentiation
to death. The z-VAD-fmk did not demonstrate any significant toxicity
toward U937 cells in the absence of TPA. In contrast, z-VAD-fmk-induced inhibition of TPA-mediated U937 cell differentiation was related to a dose- and time-dependent cell death. This death was
characterized by plasma membrane disruption, as assessed by trypan blue
staining (Figure 7A-B) and permeability
to propidium iodide (Figure 7C), whereas PARP remained uncleaved
(Figure 7D). Using dihydroethidine as a substrate for measuring
hydrogen peroxide in a flow cytometry assay, we observed that the
production of radical oxygen species (ROS) associated with the
TPA-induced differentiation process was significantly increased in
cells cotreated with z-VAD-fmk (Figure 7E). Similar results were
obtained by adding z-VAD-fmk (100 µM) to human monocytes exposed to
M-CSF, which slightly increased ROS production (Figure
8A) and induced cell death attested by trypan blue staining (Figure 8B). In both TPA-treated U937 cells and
M-CSF-treated monocytes, inhibition of ROS production by addition of
25 mM N-acetylcysteine prevented both cell death induced by 100 µM z-VAD-fmk, as attested by trypan blue exclusion, and the differentiation process (not shown).
Several proteins that influence cell viability are also key determinants in cell proliferation and differentiation.27 This has been extensively demonstrated with the Bcl-2 family of proteins. These proteins, which modulate activation of the caspase cascade in response to various apoptotic stimuli,28 also interfere with cell cycle progression29 and cell differentiation30; for example, mcl-1 was identified as an early-induced gene in ML-1 human myleoblastic leukemia cells undergoing phorbol ester-induced differentiation,30 interacts with proliferating cell nuclear antigen,31 and negatively interferes with cell death pathways.27 The present study demonstrates that activation of caspases, a central event in many cell death processes, also occurs during the differentiation of monocytes into macrophages, in the absence of apoptosis. This activation appears to be specific because it is not observed during the differentiation of monocytes into dendritic cells. The caspase activation pathway involves the mitochondrial release of cytochrome c and is delayed by overexpression of Bcl-2 and the caspase inhibitory protein p35. In addition, high doses of the broad caspase inhibitor z-VAD-fmk induces a switch from cell differentiation to cell death. Altogether, these results argue for an active role of caspases in the maturation of macrophages. Besides their extensively studied role in apoptosis, caspases have been involved in cytokine maturation and cell cycle regulation.32 In addition, these enzymes have been shown to play an active role in the differentiation of erythroblasts,9-11 lens epithelial cells,12,13 and keratinocytes.14 All these cells lose their nucleus and other organelles upon terminal differentiation.32 These events were regarded as a caspase-mediated incomplete apoptotic process because they can be blocked by caspase inhibitors and Bcl-2 overexpression. We show here that a limited activation of caspases can be detected in monocytes undergoing differentiation into macrophages, a process that does not end with enucleation. A role for caspases has been suspected in other differentiation processes; for example, overexpression of the CrmA viral caspase inhibitor abrogates osteosarcoma cell differentiation induced by a synthetic triterpenoid.33 Coexpression of the various homologs of caspases, redundancies in the pathways, and premature death of animals could have prevented identification of the role of caspases in some terminal differentiation pathways such as that leading to macrophages when studying the phenotype of caspase gene knockout mice.34,35 TPA ability to trigger the differentiation of U937 monocytic cells into
macrophages was demonstrated more than 15 years ago.20 However, not all the U937 cell clones respond equally to phorbol esters. In our hands, exposure of U937 cells (CRL-1593.2 from ATCC) to
20 nM TPA induces their strong adhesion to the culture flask and
increases CD11b expression on their plasma membrane16,21 without inducing significant cell death. Other groups have described an
apoptotic response of U937 cells to TPA36 that involves
TNF- Differentiation-related caspase activation may be tightly regulated to prevent cells undergoing differentiation from dying by apoptosis. A coordinated regulation of Bcl-2 and related proteins has been identified in differentiating cells38 and was proposed to control caspase activation associated with lens fiber maturation.13,39 TPA-induced U937 cell differentiation involves a rapid and transient induction of Mcl-1 that precedes caspase-3 activation, whereas the constitutive expression of Bcl-2 decreases belatedly.27,40 The specific depletion of Mcl-1 has been recently shown to induce apoptosis of TPA-treated U937 cells,41 suggesting that Mcl-1 transient induction could prevent excessive caspase activation during the first hours of the differentiation process. Then, the time-dependent decrease in Bcl-2 expression associated with U937 cell differentiation could facilitate the mitochondrial release of cytochrome c. Bcl-2 overexpression inhibits caspase-3 activation and delays the differentiation process, in accordance with the recent observation that Bcl-2 overexpression also prevents bleomycin-induced U937 cell differentiation.42 Little is known about the proteins cleaved by caspases when activated during the differentiation process. In many examples of apoptosis, one of the caspase target proteins is the nuclear enzyme PARP, a substrate for caspase-3 and related enzymes. Similarly to what is observed in apoptosis, PARP is cleaved from the 116-kDa form to an 85-kDa fragment in lens epithelial cells and erythroblasts undergoing differentiation.11-13 The protein acinus is another caspase-3 target whose cleavage generates an active fragment that contributes to nuclear chromatin condensation associated with cell death.22 Such a cleavage was identified in erythroblasts undergoing maturation.11 We show here that, in U937 cells undergoing differentiation, caspase-3 activation is associated with the appearance of an acinus active fragment similar to that observed in apoptotic cells, whereas PARP remains uncleaved. In human erythroblasts, caspase-3 activation leads to GATA-1 cleavage when induced by death receptor engagement9 while GATA-1 remains uncleaved when caspase-3 is activated along the differentiation process.11 These observations suggest that caspase-mediated cleavage of intracellular target proteins strongly depends on the cellular context, including the differentiation status. Caspase activation was not identified in human monocytes induced to differentiate into dendritic cells, indicating that caspase activation may not be a general event in cell differentiation. How these enzymes contribute to specific lineage differentiation remains a matter of speculation. First, caspase-mediated proteolytic cleavage of one or several transcription factors could play a role in the lineage-specific program of gene expression.43 Secondly, caspases could influence some of the epigenetic factors that modulate the pattern of gene expression along the differentiation pathways44; for example, the active fragment of acinus could modify the nuclear chromatin structure in a manner that facilitates macrophage lineage specification.22 Third, the cleavage of caspase substrates could generate protective signals that prevent cells undergoing differentiation from dying.45 Low levels of caspase activity, such as those identified in differentiating cells, have already been associated with such a protective effect; for example, the partial cleavage of RasGAP has been shown to generate fragments that prevent cell death.46 One of these protective effects could be to counterbalance ROS production associated with the differentiation of monocytes into macrophages. Although we cannot rule out a nonspecific effect of z-VAD-fmk, the ability of this peptide to increase the production of ROS in differentiating cells suggests that caspase activation could generate a signal that negatively regulates the redox metabolism along the differentiation process. Whatever the precise function of caspases in the process, the present study indicates that the differentiation of monocytes into macrophages is specifically associated with an activation of these enzymes. This activation must be tightly regulated to prevent premature death of cells committed to differentiate. Further studies will determine how caspases contribute to specific lineage commitment during normal hematopoiesis. These studies could also provide new insights in the mechanisms of caspase activation and abnormal differentiation associated with early phases of myelodysplastic syndromes.47,48
The authors thank Jacqueline Bréard and Françoise Sainteny for providing cell lines, Anne-Helene Lak-Hal for her help during the course of the study, and the Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Dijon, for surface marker expression analyses.
Submitted June 14, 2002; accepted July 23, 2002.
Prepublished online as Blood First Edition Paper, August 8, 2002; DOI 10.1182/blood-2002-06-1778.
Supported by grants from the Ligue Nationale Contre le Cancer (C.R.), the Société Française d'Hématologie (O.S.), and the Fondation pour la Recherche Médicale and the Conseil Régional de Bourgogne (L.D.-D.)
O.S. and C.R. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Eric Solary, INSERM U517, IFR 100, Faculty of Medicine, 7, boulevard Jeanne d'Arc, 21079 Dijon cedex, France; e-mail: esolary{at}u-bourgogne.fr.
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J. W. Darnowski, F. A. Goulette, Y.-j. Guan, D. Chatterjee, Z.-F. Yang, L. P. Cousens, and Y. E. Chin Stat3 Cleavage by Caspases: IMPACT ON FULL-LENGTH Stat3 EXPRESSION, FRAGMENT FORMATION, AND TRANSCRIPTIONAL ACTIVITY J. Biol. Chem., June 30, 2006; 281(26): 17707 - 17717. [Abstract] [Full Text] [PDF]
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S. Cathelin, C. Rebe, L. Haddaoui, N. Simioni, F. Verdier, M. Fontenay, S. Launay, P. Mayeux, and E. Solary Identification of Proteins Cleaved Downstream of Caspase Activation in Monocytes Undergoing Macrophage Differentiation J. Biol. Chem., June 30, 2006; 281(26): 17779 - 17788. [Abstract] [Full Text] [PDF]
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M. Kalamvoki, U. Georgopoulou, and P. Mavromara The NS5A Protein of the Hepatitis C Virus Genotype 1a Is Cleaved by Caspases to Produce C-terminal-truncated Forms of the Protein That Reside Mainly in the Cytosol J. Biol. Chem., May 12, 2006; 281(19): 13449 - 13462. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
20°C. Further dilutions were made in
culture medium just before use. The final concentration of DMSO in
culture medium never exceed 0.3% (vol/vol), which was nontoxic to the
cells. Human recombinant tumor necrosis factor-
(rhTNF-
m
(Figure 
nor CD11b expression increase (not shown) in U397 cells
exposed to TPA. Similarly, the blocking anti-Fas antibody ZB4
did not influence caspase-3 activation (Figure 
) before counting the percentage of
cells stained with trypan blue (
indicates U937 cells exposed
to 100 µM z-VAD-fmk in the absence of TPA). (C) U937 cells were
either left untreated or treated with TPA (20 nM, 48 hours), z-VAD-fmk
(100 µM, 48 hours), or the TPA/z-VAD-fmk combination. The percentages
of cells labeled with annexin V-FITC (left panels) and propidium
iodide (PI; right panels) were measured by flow cytometry. (D) Western
blot analysis of poly(ADP-ribose)polymerase (PARP) in cells treated as
above or with etoposide (VP16; 50 µM, 6 hours). HSC70 expression was
used for checking loading. (E) Radical oxygen species measured by flow
cytometry in cells exposed for indicated times to 20 nM TPA, in the
absence (white bars) and presence (black bars) of 100 µM z-VAD-fmk.
NAC indicates cotreatment with 25 mM N-acetyl-cysteine for 48 hours.
Mean ± SD of 3 experiments in triplicate (A,B,E) or 1 representative
of 3 independent experiments (C,D).
-inducing factor and regulates LPS-induced IFN-