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*
Department of Life and Health Sciences, Hyogo University of Teacher Education, Yashiro, Hyogo 673-1494, Japan; and
Department of Food Science and Nutrition, Nara Women’s University, Nara 630-8506 Japan
1To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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KEY WORDS: • apoptosis • DHA • tumor necrosis factor • U937 cells • vitamin E
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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).
The molecular mechanism of TNF-induced cytotoxicity has been of
great concern because of the important roles of TNF and TNF-related
ligands in several physiological and pathological conditions
(Beyaert and Fiers 1994
, Tracey and Cerami 1993
). Recent advances have fairly well established the main
route of the signaling. TNF-induced trimerization of specific
receptors and recruitment of their adapter proteins mediate the
cytotoxic action of TNF (Hsu et al. 1996
, Liu et al. 1996
). The subsequent intracellular signaling for
TNF-induced apoptosis is considered to be primarily transduced
through the latent machinery commonly utilized by other
apoptosis-inducing stimuli such as Fas activation or cellular
stress (Green 1998
). However, TNF could not lead all of
the TNF receptor-bearing cells to apoptosis, suggesting that there
is some mechanism to rescue the cells from apoptosis. Endogenous
inhibitors of caspases may prevent undesirable activation of the
caspase cascade (Koseki et al. 1998
, Seol and Nunez 1999
). Several lines of evidence indicate that
TNF-binding to specific receptors also elicits the signaling to
prevent cell death through activating NF
B (Beg and Baltimore 1996
, Liu et al. 1996
, Van Antwerp et al. 1996
, Van Antwerp et al. 1998
, Wang et al. 1996
). Manganese superoxide dismutase participates in
resistance to the cytotoxicity of TNF (Manna et al. 1998
, Wong et al. 1989
), probably because
reactive oxygen species (ROS) are critical signaling molecules in
TNF-induced apoptosis. Furthermore, relatively nonspecific
chemicals or nutrients show activity for exogenously attenuating
TNF-induced apoptosis. Zinc significantly inhibits TNF-induced
apoptosis (Fady et al. 1995
) probably because of its
role as a potent inhibitor of caspase 3 (Perry et al. 1997
). Synthetic antioxidants, butylated hydroxyanisol
(Brekke et al. 1992
, Goossens et al. 1995
) and N-acetyl-L-cystein
(Mayer and Noble 1994
) block cell death mediated by TNF.
Vitamin C may be able to reduce apoptotic cell death, because ascorbate
and ascorbate free radicals can potentiate NFB activation
(Munoz et al. 1997
).
Dietary (n-3) fatty acids, abundant in fish oil, have been reported to
possess the potential to reduce chronic inflammatory diseases through
attenuating activities of inflammatory lipid mediators or
pro-inflammatory cytokines including TNF. Intake of docosahexaenoic
acid [DHA, 22:6(n-3)] and eicosapentaenoic acid [EPA, 20:5(n-3)]
can reduce the generation of eicosanoids derived from arachidonic acid
[AA, 20:4(n-6)] (Simopoulos 1991
). Several human
studies have shown that supplementation of (n-3) fatty acids in the
diet results in reduced ex vivo production of TNF (Calder 1997
). Furthermore, there is evidence raising the possibility
that (n-3) fatty acids could affect the cellular response to cytokines,
especially cytolysis induced by TNF. It has been suggested that AA
release may be involved in the cytotoxic action of TNF
(Palombella and Vilcek 1989
, Suffys et al. 1987
). Recent findings indicate that AA-specific type IV
cytosolic phospholipase A2 (cPLA2) may play an
essential role in TNF-induced apoptosis (Enari et al. 1996
, Hayakawa et al. 1993
,
Voelkel-Johnson et al. 1996
, Wissing et al. 1997
, Wu et al. 1998
). These observations imply
that supplementation of (n-3) fatty acid may affect cytolysis caused by
TNF, because DHA and/or EPA inhibit AA metabolism at various enzymatic
steps (Simopoulos 1991
). Especially, DHA possesses
distinctive inhibitory activity against cPLA2
(Shikano et al. 1993
, 1994
). However, in
contrast to the regulatory activity of (n-3) fatty acids on the
synthesis of TNF, effect of (n-3) fatty acids on cellular response to
cytotoxic action of TNF has not been fully investigated.
In this study, we examined the effect of supplementation of DHA, EPA
and AA to human monocytic U937 cell cultures on the apoptosis induced
by TNF. As observed in our previous study using sphingosine as an
apoptosis-inducing agent (Kishida et al. 1998
), only
DHA showed the potent ability to attenuate TNF-induced apoptosis.
Furthermore, the synergistic effect of vitamin E, the principal
antioxidant vitamin that has been reported to reduce cell death
elicited by various apoptotic stimuli (Barroso et al. 1997
, Haendeler et al.1996
, Ikeda et al. 1999
, Straface et al. 1995
), was examined to
assess to what extent nutrients can attenuate TNF-induced
apoptosis. Our data indicated that, even though the main signal
transducing system for TNF-induced apoptosis is considered to be
precisely programmed through protein/protein interaction (Green 1998
), DHA and vitamin E can separately or synergistically
reduce the proportion of apoptotic cells. These results imply that
nutrients could regulate pathophysiological conditions in which
TNF-induced apoptosis plays an important role.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Fatty acid-free bovine serum albumin (BSA), AA, EPA, DHA and
bisbenzimide (Hoechst 33342) were purchased from Sigma (St. Louis, MO).
-Tocopherol (vitamin E), cycloheximide (CHI) and Proteinase K were
from Wako Pure Chemicals (Osaka, Japan). RNase A and SYBR Green were
from Takara Biochemical (Ohtsu, Japan) and Molecular Probes Inc.
(Rockland, ME), respectively. RPMI 1640 medium, fetal bovine serum
(FBS), L-glutamine and kanamycin were obtained from Gibco
BRL (Grand Island, NY). TNF was from Boehringer Mannheim Biochemica
(Germany). Arachidonoyl trifluoromethylketone
(AACOCF3) and methyl
arachidonoylfluorophosphonate (MAFP) were from Biomol Research
Laboratory (Plymouth Meeting, PA) and Caymman Chemical (Ann Arbor, MI),
respectively.
Cell culture.
Human monocytic U937 cells were obtained from the Riken Cell Bank (Tsukuba, Japan). Cells were maintained in RPMI 1640 medium containing 10% heat-inactivated FBS, L-glutamine and kanamycin (10% FBS-RPMI1640) at 37°C in a humidified atmosphere of 5% CO2 and subcultured every 5 or 6 d. In the preincubation with various supplements or stimulation with TNF and CHI, 10% FBS-RPMI1640 was used as culture medium, but cells were stimulated in serum-free medium by TNF without CHI.
Induction of apoptosis and effect of supplementation of fatty acid and/or vitamin E.
Fatty acid (AA, EPA or DHA) was conjugated with fatty acid-free BSA in a 1:5 M ratio. A stock solution of vitamin E was prepared in ethanol. Cells (1.0 x 106 cells/mL) were incubated in 10% FBS-RPMI1640 supplemented with the fatty acids and/or vitamin E for 24 h. Cell viability is affected by high concentration of ethanol or vitamin E. However, we confirmed that the incubation with 1 mmol/L vitamin E did not affect the viability, and kept cell growth normally under our preincubation condition. In the stimulation with TNF alone, cells were washed after the preincubation, suspended at a density of 2 x 106 cells/mL in serum-free medium and allowed to re-equilibrate for 1 h without the supplements. Cells were then treated with TNF (100 µg/L) for 3 h. In the stimulation with TNF + CHI, cells were washed after the preincubation, suspended in 10% FBS-RPMI1640 (2 x 106 cells/mL) and prewarmed for 1 h without the supplements. Apoptosis was induced with a combination of TNF (0.5–2.0 µg/L) and CHI (1 mg/L). In this concentration of CHI, maximal induction of apoptosis was observed with fixed concentration of TNF, and higher amounts of CHI in the combination of TNF reduced apoptotic cell percentage. Without TNF, this concentration of CHI reduced cell growth to 10% of that without CHI, indicating that protein synthesis was reduced, but not completely inhibited by this concentration of CHI.
Assay of apoptosis.
Morphological changes in the nuclear chromatin of cells undergoing
apoptosis were detected using an Olympus IMT2-RFL fluorescence
microscope after fixation and staining with bisbenzimide (Hoechst
33342) as described previously (Kishida et al. 1997
).
Data were expressed as means ± SD for at least three
independent analyses. The inhibition rate of apoptosis was calculated
as follows: 100 x {(A - B) - (C
- D)}/(A - B). A is
percentage apoptosis by the inducer (TNF); B is percentage
of apoptosis by the vehicle of the inducer; C is percentage
apoptosis in the presence of both the inducer and the inhibitor;
D is percentage apoptosis in the presence of the inhibitor.
DNA fragmentation was assessed by agarose gel electrophoresis as
described previously (Kishida et al. 1997
). Briefly,
cells (1 x 106 cells) were lysed in 0.5% Triton X
containing 10 mmol/L Tris-HCl (pH7.4) and 5 mmol/L EDTA for 20 min
on ice. The lysate was centrifuged at 27000 x g for 15
min at 4°C. The supernatant was treated with Proteinase K (100 µg).
DNA in the supernatant was extracted with phenol-chloroform and
precipitated with 0.3 mol/L sodium acetate and 80% ethanol at
-20°C. The DNA was treated with RNase A, prior to loading onto a
2.0% agarose gel (6 x 104 cells/lane). DNA bands were
visualized under UV light after staining with SYBR Green.
Effect of cPLA2 inhibitors on the apoptosis induced by TNF.
AACOCF3 or MAFP was dissolved in DMSO and added to the cell suspension at the final concentration of 10 µmol/L. The final concentration of DMSO was 0.1%. After the addition of AACOCF3 or MAFP, cells were preincubated for 1 h in the presence of 10% FBS, and TNF (2 µg/L) and CHI (1 mg/L) were then added without changing the medium.
Lipid analysis.
Cell lipids were extracted by the method of Bligh and Dyer (1959)
and
separated by TLC as described previously (Shikano et al. 1994
). The bands corresponding to phospholipids were scraped
from the plates. The fatty acid esters of phospholipids were converted
to methyl esters and quantified by gas chromatography with a capillary
column as described previously (Kishida et al. 1998
).
Statistical methods.
All statistical analyses were carried out using SPSS (version 9.0; SPSS Inc., Chicago, IL) software. After ascertaining the values to be homoscedastic by Levene’s test, one-way or two-way ANOVA was applied. Difference of each group mean from control value was analyzed using Dunnett’s t posthoc procedure. When the values were not homoscedastic, Kruskal-Wallis test was applied for the analysis instead of ANOVA, and difference between two groups was analyzed by Dunnett’s T3 procedure.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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shows the effect of the preincubation with 10 µmol/L DHA, EPA and AA
for 24 h on fatty acid level of phospholipids in human monocytic
U937 cells. Supplementing each PUFA to the cell culture enriched the
corresponding PUFA in the phospholipids of U937 cells. In addition to
the PUFA corresponding to the one supplemented, docosapentaenoic acid
[22:5(n-3)] increased in cells preincubated with EPA. The increase in
each PUFA was concomitant with decreases in oleic (18:1) and
palmitoleic acids (16:1), probably reflecting a high level of these
monoenoic fatty acids in U937 cells. DHA significantly decreased the
cellular level of AA by its supplementation, but the reduction was only
11% of the level without supplementation. Figure 1
shows the effect of preincubation with PUFA on the apoptosis induced by
TNF. Under serum-free conditions, 100 µg/L TNF induced apoptosis
in 16% of the cells precultured without fatty acid supplementation
(Fig. 1A)
. This apoptotic cell percentage was almost maximum when U937
cells were stimulated by TNF without CHI. Preincubation with AA did not
change the apoptotic cell percentage. EPA slightly but significantly
decreased the proportion of apoptotic cells. On the other hand,
preincubation with DHA greatly (55%) attenuated apoptosis. To assess
the effect of fatty acid treatment on the apoptosis with higher
frequency, we co-supplemented CHI with TNF for induction of apoptosis.
Figure 1B
shows the effect of PUFA on the apoptosis induced by 0.5
µg/L TNF with CHI in 10% FBS-added culture medium. In this case,
supplementation of neither AA nor EPA affected apoptosis of U937 cells.
Only DHA attenuated apoptosis. Repeated experiments revealed the
reproducibility of the inhibitory activity of DHA against TNF (0.5
µg/L)+CHI-induced apoptosis, and the inhibition rate ranged from 40
to 70%.
|
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). In addition, vitamin E, another nutrient that has been postulated to
attenuate apoptosis (Barroso et al. 1997
,
Haendeler et al. 1996
, Ikeda et al. 1999
,
Straface et al. 1995
), was also examined regarding its
ability to attenuate TNF + CHI-induced apoptosis (Fig. 2B)
.
Preincubation of U937 cells with 4 µmol/L DHA significantly reduced
the apoptotic cell percentage, and the inhibition rate was ~20%. In
these cells, the DHA content in phospholipid was 80% of that observed
in 10 µmol/L DHA-supplemented cells (data not shown). However,
the ability of DHA to inhibit apoptosis seemed to be limited, because
20 µmol/L DHA did not show stronger activity than 10 µmol/L DHA.
This was not due to the restricted incorporation of DHA into U937 cells
because supplementation of 20 µmol/L DHA increased the DHA content in
phospholipids to 14% of the total fatty acid. Supplementation of
vitamin E could also attenuate TNF-induced apoptosis, and this
ability was significant at a concentration of 0.25 mmol/L. However,
increasing the concentration to > 1.0 mmol/L did not further
decrease apoptotic cell percentage. These results indicated that a
nutrient, such as DHA or vitamin E, could play a role as a partial
inhibitor of TNF-induced apoptosis.
|
).
Vitamin E is a potent radical scavenger. Such differences in probable
functions of these two nutrients imply that DHA and vitamin E could act
synergistically in the attenuation of apoptosis. This possibility was
ascertained by examining the combined effect of DHA and vitamin E on
the apoptosis induced by various doses of TNF with or without CHI
(Table 2
). DHA and vitamin E were inhibitory. In addition, co-supplementation of
these nutrients further decreased significantly the proportion of
cells. The inhibitory effect of DHA and/or vitamin E on apoptosis was
further confirmed by electrophoretic analysis of fragmented DNA
(Fig. 3
). As predicted by the microscopic analysis, preincubation with DHA or
vitamin E did not completely inhibit the DNA fragmentation induced by
0.5 µg/L TNF + CHI. However, formation of the DNA ladder was reduced
in the cells preincubated with one of these nutrients.
Co-supplementation of both nutrients inhibited ladder formation to a
greater extent.
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to precisely assess TNF-induced cell death. During the time course,
necrosis was negligible when assessed by the trypan blue dye exclusion
test. Preincubation with DHA and/or vitamin E significantly
(P < 0.01) increased intact cells observed within
6 h. An additive effect of DHA and vitamin E was significant
(P < 0.01 vs. DHA or vitamin E treatment) only at
the 3-h incubation time point. However, the percentage of intact cells
treated with both DHA and vitamin E was always higher than those
observed in cells preincubated with only one of these nutrients.
Preincubation with either DHA or vitamin E did not significantly
increase intact cell percentage observed 9 h after TNF addition,
but cell survival was significantly improved by co-supplementation of
DHA and vitamin E, even at this time point.
|
). This suggested
that DHA could attenuate Ca-sensitive and AA-selective
PLA2 activity. In fact, an in vitro experiment showed that
DHA-containing phospholipid could reduce the hydrolysis of
arachidonate by Ca-sensitive and AA-selective cPLA2
(Shikano et al. 1994
). Such an activity of DHA may
explain how DHA attenuates TNF-induced apoptosis, because it has
been suggested that cPLA2 may play a crucial role in signal
transduction for TNF-induced cytotoxicity (Enari et al. 1996
,Hayakawa et al. 1993
, Johnson et al.
1996, Wissing et al. 1997
, Wu. et al. 1998
). Although we have not yet definitely determined the role
of cPLA2 in TNF signaling and the effect of DHA
supplementation on the activity, evidence to support the contribution
of cPLA2 in TNF-induced apoptosis is shown in
Table 3
. In this experiment, the effect of cPLA2 inhibitors on
apoptosis was examined. AACOCF3, a specific inhibitor of
cPLA2, attenuated apoptosis induced by TNF and CHI.
However, AACOCF3 did not completely inhibit the apoptosis,
and the inhibition rate was 60.7%. A similar inhibition rate (61.9)
percentage against TNF-induced apoptosis was obtained in the
treatment with MAFP, an inhibitor of both cPLA2 and type IV
Ca-independent phospholipase A2. These results indicate
that inhibiting cPLA2 can exert almost the same effect as
preincubation with DHA. Our previous study suggested that
DHA-containing phospholipid could reduce cPLA2 activity
(Shikano et al. 1994
). Taken together, it seems likely
that the attenuation of TNF-induced apoptosis by the preincubation
with DHA is due to the inhibition of cPLA2 activity,
although the precise mechanism should be further explored.
|
).
Similarly, when TNF was used as an apoptosis-inducing agent in the
present study, only DHA appeared to be able to reduce the proportion of
apoptotic cells (Fig. 1)
. Under some incubation conditions, unsaturated
fatty acids were reported to induce apoptosis (Lai et al. 1996
, Seegers et al. 1997
) or inhibit cell
proliferation (Jayadev et al. 1994
). We observed that
DHA, EPA and AA exhibited cytotoxicity when these fatty acids were
added to the culture in high amounts compared with the BSA or serum
protein level (data not shown). Under our preincubation conditions, DHA
supplementation was not cytotoxic, but provided cellular resistance to
TNF-induced apoptosis after 24 h. During the preincubation,
DHA esterified in phospholipids significantly increased (Table 1)
, but
the level of its free acid form did not change (data not shown). Since
DHA had to be preincubated to show the activity, DHA probably acts
after esterification into membrane phospholipids. This
supported our hypothesis that DHA attenuates TNF-induced apoptosis
by inhibiting cPLA2 because DHA-containing
phospholipid, but not free DHA, could reduce AA release from
phospholipid by cPLA2 (Shikano et al. 1994
). In the
stimulation by TNF without CHI, EPA showed much lower but significant
inhibitory activity. Weak activity of EPA to reduce TNF-induced
apoptosis might be due to an increase of docosapentaenoic acid, another
C22 fatty acid, during preincubation. However, reduction of
apoptosis by EPA was not observed in the stimulation with TNF and CHI.
Docosapentaenoic acid retained during the preincubation with EPA might
be insufficient to reduce apoptosis induced with stronger stimulation.
Vitamin E is an effective scavenger of oxygen radicals and alkyl
radicals. However, when added to the cell culture, it takes several
hours for a detectable amount to enter into the cells (Ikeda et al. 1999
). Therefore cells were preincubated with vitamin E for
24 h which was thought to be sufficient to elevate intracellular
vitamin E. During this preincubation, vitamin E can reduce the
peroxidation of PUFA in cell culture. This may explain the inhibitory
activity of vitamin E and the synergistic effect with DHA. However,
N-acetylcysteine or 2-mercaptoethanol, a synthetic
antioxidant, added to the cell culture simultaneously with TNF and CHI
significantly inhibited TNF-induced apoptosis (Yano, M., Kishida,
E., and Masuzawa, Y., unpublished observation). This implies that the
effectiveness of another antioxidant, vitamin E, is not only due to the
suppression of lipid peroxidation during preincubation. It is most
likely that vitamin E scavenged ROS generated by TNF stimulation and
consequently reduced TNF-induced apoptosis solely or
synergistically with DHA.
At the present time, it is unclear whether apoptosis induced by various
stimuli is harmful or beneficial in various physiological and
pathological circumstances. Induction of apoptosis and subsequent
ingestion of apoptotic cells by macrophages may prevent dangerous
immune responses or inflammation (Fadok et al. 1998
,
Gao et al. 1998
, Orteu et al. 1998
). On
the contrary, it has been reported that caspase inhibitors can protect
against ischemia of the liver (Cursio et al. 1999
) and
brain (Cheng et al. 1998
). TNF-induced apoptosis may
participate in rejection of organ transplants (Morel et al. 1993
), chronic hepatitis (Bradham et al. 1998
)
and acute pancreatitis (Norman 1998
). Our observations
indicate that nutrients such as DHA and vitamin E can attenuate
TNF-induced apoptosis of cultured cells. Taken together, it is
conceivable that ingestion of nutrients such as DHA and vitamin E can
reduce TNF-induced apoptosis and subsequently exert a beneficial
effect on organ dysfunction associated with various diseases.
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FOOTNOTES |
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Manuscript received September 9, 1999. Initial review completed October 13, 1999. Revision accepted December 15, 1999.
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