By
§
From the * Department of Immunology and Parasitology, Yamagata University School of Medicine,
Yamagata 990-9585, Japan; the Department of Molecular and Cellular Biology and the § Laboratory
of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University,
Fukuoka 812-8582, Japan; and the
Department of Dermatology, Gunma University School of
Medicine, Maebashi 371-8511, Japan
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Abstract |
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To elucidate the role of A1, a new member of the Bcl-2 family of apoptosis regulators active in
hematopoietic cell apoptosis, we established mice lacking A1-a, a subtype of the A1 gene in mice (A1-a/
mice). Spontaneous apoptosis of peripheral blood neutrophils of A1-a
/
mice
was enhanced compared with that of either wild-type mice or heterozygous mutants (A1-a+/
mice). Neutrophil apoptosis inhibition induced by lipopolysaccharide treatment in vitro or
transendothelial migration in vivo observed in wild-type mice was abolished in both A1-a
/
and A1-a+/
animals. On the other hand, the extent of tumor necrosis factor
-induced acceleration of neutrophil apoptosis did not differ among A1-a
/
, A1-a+/
, and wild-type mice.
The descending order of A1 mRNA expression was wild-type, A1-a+/
, and A1-a
/
. Taken
together, these results suggest that A1 is involved in inhibition of certain types of neutrophil
apoptosis.
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Introduction |
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Control of neutrophil function seems important for retaining an effective level of bacterial killing and other
physiological properties while avoiding damage to normal
tissues. The short life of neutrophils may ensure fulfillment
of the latter requirement, since an early death after accomplishing their physiological task may prevent possible damage to normal tissues, which might occur with a prolonged
survival of these cells. However, there are situations that
require neutrophils to function actively for an extended period, such as during bacterial infection. In fact, these cells have been found to survive for longer periods in various
situations. We have demonstrated previously that apoptosis
of peritoneal exudate neutrophils (PEN)1 and peripheral
blood neutrophils (PBN) obtained from rats intraperitoneally injected with inflammatory agents is severely inhibited (1). On the other hand, certain agents accelerate apoptosis of these cells. TNF- enhances apoptosis of human (2)
and rat (1) neutrophils, and PMA induces prompt neutrophil death, although in a different manner from that of typical apoptosis or necrosis (3). However, the mechanisms responsible for the regulation of neutrophil apoptosis remain
largely unknown.
Several genes have been implicated in the regulation of
cell death, including those of the bcl-2 family (4), Fas/
Apo1 (10, 11), c-myc (12), p53 (13), and nur77 (14). Bcl-2, the bcl-2 product, blocks or delays cell death after administration of death-inducing agents or growth factor withdrawal (4). Analysis of bcl-2-deficient mice provided evidence that bcl-2 is required for ensuring the full life span of
mature lymphocytes in vivo (15). A newly recognized
member of the bcl-2 family, A1, was originally isolated
from a cDNA library prepared from GM-CSF-treated mouse bone marrow cultures. Murine A1 is expressed in
the thymus, spleen, and bone marrow, and specifically in
the hematopoietic cell lineages including Th cells, macrophages, and neutrophils (9). Recently, a role for A1 in
protection against apoptosis was reported (18). It has
also been demonstrated that A1 is the only known Bcl-2
family member to be induced by the inflammatory cytokines TNF- and IL-1
(21).
It has been shown that Bcl-2 and Bcl-xL can inhibit most
apoptosis. Both of these proteins are absent in mature neutrophils although Bcl-2 is expressed in early myeloid cells
of the bone marrow (22). Expression of a newly recognized
member of the Bcl-2 family, A1, alone of all the known
proteins that inhibit neutrophil apoptosis, suggests that A1
plays a major role in the prevention of this apoptosis. We
have reported previously that in the murine genome A1
consists of at least four genes, A1-a, -b, -c, and -d (23), all
of which have a high degree of homology with each other
at the nucleotide and amino acid sequence levels. In this
study, we used gene targeting to establish mice lacking A1-a, one of the A1 subtypes (A1-a/
mice), in order
to investigate the possible role of A1-a in the regulation
of neutrophil apoptosis. We describe here acceleration of
neutrophil apoptosis in A1-a
/
mice and discuss its possible mechanisms.
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Materials and Methods |
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Establishment of the A1-a/
Mouse.
Animals.
A1-aPreparation of PBN.
We separated PBN from blood using a partially modified method of Tsuchida et al. (1). Heparinized peripheral blood was obtained by cardiac puncture. Blood from three to seven mice of the same group was usually pooled together to obtain a sufficient number of PBN for the apoptosis assay. RBCs were sedimented by the addition of an equal volume of 3% (wt/vol) dextran T-500 (25) (Pharmacia Biotech AB, Uppsala, Sweden) in PBS. The mixture of blood and dextran was allowed to stand in a 15-ml conical tube (Falcon FAL2096; Becton Dickinson Labware, Lincoln Park, NJ) at room temperature for 12-15 min to permit the erythrocytes to sediment. The leukocyte-rich supernatant (buffy coat) was transferred to another conical tube which was then filled with Eagle's MEM (Nissui Pharmaceutical Co., Ltd., Tokyo, Japan) and centrifuged at 650 g for 5 min at 4°C. The leukocyte-rich erythrocyte layer at the bottom was suspended in 5 ml of MEM and centrifuged on 5 ml of Ficoll-Paque (specific gravity, 1.077; Pharmacia Biotech AB) at 800 g for 10 min at 4°C. The erythrocytes in the pellet were lysed by hypotonic shock. Neutrophils were washed with MEM, resuspended in RPMI 1640 medium (GIBCO BRL, Gaithersburg, MD) supplemented with 10% FCS (Whittaker M.A. Bioproducts, Inc., Walkersville, MD), and used for experiments. The purity obtained was ~85-95%.Preparation of PEN.
Mice were injected intraperitoneally with 4-5 ml of 3% proteose peptone (Difco Laboratories Inc., Detroit, MI). 12 h later each mouse received the same injection again. 3 h after the second injection mice were killed and PEN were harvested twice by peritoneal lavage with 4 ml of cold heparinized MEM. The cell suspension was washed by centrifugation at 650 g for 5 min at 4°C and the pellet was resuspended in 5 ml MEM and centrifuged on 5 ml of Ficoll-Paque at 800 g for 10 min at 4°C. The neutrophils were washed with MEM and resuspended in RPMI 1640 supplemented with 10% FCS and then used for experiments. The approximate purity obtained was >95%.Neutrophil Culture.
Aliquots (0.4 ml) of neutrophil suspensions (0.5 × 106/ml) were seeded into 8-well culture slides (Falcon FAL4118; Becton Dickinson Labware) and incubated at 37°C for varying periods of time in a 5% CO2 atmosphere. Neutrophils were cultured in the presence or absence of recombinant human TNF-Examination of Neutrophil Apoptosis.
Neutrophils incubated under specific conditions were stained with May-Giemsa and apoptotic cells were counted under light microscopy (×1,000). Representative microscopic images of normal and apoptotic neutrophils are shown in Fig. 1. Approximately 300-1200 cells were scanned per specimen.
|
Detection of A1 mRNA by RT-PCR and Its Quantification by Competitive RT-PCR.
To detect A1 mRNA, the total RNA (1 µg) isolated from neutrophils was reverse transcribed with AMV reverse transcriptase (TaKaRa, Ohtsu, Japan) using an oligo dT primer. First-strand cDNA synthesis products were amplified in reaction volumes of 50 µl using the primers 5'-AATTCCAACAGCCTCCAGATATG-3' and 5'-GAAACAAAATATCTGCAACTCTGG-3', together with 0.625 U Ex-Taq polymerase (TaKaRa) in a DNA Thermal Cycler (Perkin-Elmer Corp., Norwalk, CT). PCR products were digested with 10 U of the restriction enzymes, BglII and NsiI (Boehringer Mannheim Biochemicals, Indianapolis, IN), to distinguish each subtype, and then electrophoresed on 2% agarose gels. The agarose gel image was captured by densitometer and relative quantification of each band was determined by NIH image analysis. To quantify A1 mRNA, a competitive RT-PCR was performed. The DNA competitor was amplified fromData Analysis.
Results were expressed as means of at least five independent experiments. Statistical significance was determined by the unpaired t test. ![]() |
Results |
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The murine A1 genomic locus is
comprised of two exons spanning ~4.5 kb. The targeting
construct was designed to delete the protein coding region
of exon 1 (Fig. 2 A). Electroporation of the linearized targeting vector and G418/gancyclovir selection for homologous recombinants were carried out as described in Materials and Methods. G418/gancyclovir double-resistant ES
cell clones (67 clones) were screened for homologous recombination events by PCR, and two clones (3.0%) were
found to have recombined homologously. All of these
clones were confirmed by Southern blot analysis to contain
the desired targeted allele (Fig. 2 B). The two clones were
injected into C57BL/6 blastocysts, and high coat-color
chimeric males that transmitted the mutant allele to the
germline were obtained. Heterozygous offspring of chimeras appeared entirely normal and were fertile. To determine
the relative expression level of mRNA of each A1 subtype,
RNA obtained from neutrophils was amplified. The RT-PCR products were then digested with the restriction
enzymes BglII and NsiI to distinguish each subtype. Expression ratios of each subtype were as follows: among the
A1-a/
mice, the A1-b/A1-d ratio was 3:2; and in A1-a+/
mice, the A1-a/A1-b/A1-d ratio was 4:7:6 (data not
shown). Ratios for wild-type mice were as follows: among
C57BL/6 mice, the A1-a/A1-b/A1-d ratio was 3:4:3; and
in 129Sv mice, this ratio was 7:8:5 (23).
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Heterozygote matings yielded
wild-type (+/+), heterozygous (+/), and nullizygous
(
/
) offspring at roughly the expected Mendelian ratio,
thus indicating no significant embryonic lethality. At birth,
these homozygotes were indistinguishable from their wild-type and heterozygous littermates. However, aging caused hair loss on the head and face of both A1-a
/
and A1-a+/
mice by 8-12 wk of age (Fig. 3).
|
Despite the hair loss, the outward appearance of A1-a/
and A1-a+/
mice was normal (Fig. 3). There was no evidence of illness in either of these groups in mice up to 12 mo of age.
Several groups have reported that transfection of A1
into cell lines prolongs cell survival (18). However, there
has been no report evaluating the relationship between endogenous A1 and apoptosis. To determine whether A1-a
plays a role in neutrophil apoptosis, we studied the spontaneous apoptosis of PBN obtained from A1-a/
mice. We first
examined spontaneous apoptosis of PBN from control C57BL/6 and 129Sv mice. Since there was no difference in
PBN apoptosis within these two strains (data not shown),
we used mice of these groups as wild-type controls. Spontaneous apoptosis of PBN obtained from wild-type and
A1-a+/
mice gradually increased during incubation in
vitro, and there was no significant difference between these
two groups. On the other hand, spontaneous apoptosis of
PBN from A1-a
/
mice was significantly greater than that
of wild-type or A1-a+/
mice at 12 and 24 h of incubation
(Fig. 4).
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We and others have
demonstrated that neutrophil apoptosis is modulated according to the conditions under which the cell is placed (1,
26). To determine whether regulation of apoptosis in
similar situations can occur in A1-a/
mice, we examined
both the level of apoptosis of PEN, which was found to be
lower than that of PBN in normal rats (1), and the level of
apoptosis of PBN treated with LPS, which has been shown
to be significantly inhibited in human preparations (26, 27).
Table 1 shows that, in wild-type mice, apoptosis of neutrophils under the two sets of conditions mentioned above
(PEN and LPS treatment) was significantly lower than that
of untreated PBN, as already reported (1, 26, 27). On the
other hand, in A1-a
/
and A1-a+/
mice, apoptosis of
PEN and LPS-treated PBN was not inhibited compared
with that of untreated PBN. These results indirectly suggest
that A1-a may be at least partially involved in neutrophil apoptosis suppression induced by LPS treatment in vitro
and transendothelial migration in vivo. Furthermore, when
apoptosis of PEN and LPS-treated PBN were compared in
A1-a
/
, A1-a+/
, and wild-type mice, the descending order of apoptosis was A1-a
/
, A1-a+/
, and wild-type,
with significant differences observed among these groups at
12 h of incubation (Table 1).
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The above results show that
neutrophil apoptosis is upregulated in both A1-a/
and
A1-a+/
mice. To begin to clarify the mechanisms involved in this phenomenon, we examined the relative
expression of A1 mRNA in neutrophils obtained from
mice of different genotypes. By competitive RT-PCR, the
amount of A1 mRNA in neutrophils was most prominent
in wild-type mice, second in A1-a+/
mice, and smallest in
A1-a
/
mice (Table 2), suggesting that the level of neutrophil apoptosis in certain situations may be reflected by
the level of A1 mRNA expression in these cells.
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The finding that spontaneous apoptosis of PBN and
PEN was enhanced in A1-a/
mice (Table 1) led us to
speculate that the number of PBN and PEN in A1-a
/
mice might be smaller than in wild-type mice. To answer
this question, we determined the number of PBN in untreated A1-a
/
, A1-a+/
, wild-type C57BL/6, and
129Sv mice. Unexpectedly, the number of PBN in these
mice did not differ. Furthermore, using these four different
strains of mice, we examined the number of PBN and PEN
at 3, 6, 12, 24 h, as well as 3 h after a booster injection at 12 h
after intraperitoneal injection of proteose peptone. The number of PBN and PEN in the four groups did not significantly differ from each other at any of the time points after
the injection of the reagent (data not shown).
We demonstrated previously
that TNF- enhances apoptosis of human (2) and rat (1)
neutrophils. To further explore possible mechanisms for
the enhancement of spontaneous apoptosis of PBN in A1-a
/
mice, we examined the sensitivity of these PBN in
terms of TNF-
enhancement of apoptosis. Treatment
with this cytokine enhanced PBN apoptosis in all wild-type, A1-a+/
, and A1-a
/
mice at a 12 h incubation (Fig.
5). The extent of apoptosis enhancement by TNF-
was
not significantly different among these three groups of mice
(data not shown). On the other hand, apoptosis of PEN was not enhanced in any of the A1-a
/
, A1-a+/
, or wild-type mice by TNF-
(Fig. 5), similar to our results obtained previously with normal rats (1).
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Discussion |
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After establishing A1-a/
mice in this study, we were
able to show that spontaneous apoptosis of PBN and PEN
is enhanced in these animals. Although the mechanisms
governing the short life span of neutrophils and their
prompt spontaneous apoptosis remain obscure, downregulation of bcl-2 expression during the terminal phase of neutrophilic differentiation (31, 32) could largely account for
the above phenomenon. It is well known that Bcl-2 inhibits apoptosis of many types of cells (4, 33) and that neutrophil apoptosis is inhibited in bcl-2 transgenic mice (34). However, other members of the Bcl-2 family are also
involved in inhibiting apoptosis of various cells in certain
situations. Bcl-xL, a member of the Bcl-2 family, prevents immunosuppressant-induced mature B cell apoptosis,
whereas Bcl-2 is not involved in this phenomenon (35).
Furthermore, Mcl-1, another member of the Bcl-2 family,
delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells (36). In this sense, A1, a new
member of the Bcl-2 family, may be a main suppressor of
neutrophil apoptosis for the following reasons: (a) transfection of A1 into various types of cells inhibits apoptosis (18-
20); (b) A1 is stably induced during G-CSF-stimulated
neutrophilic differentiation of a myeloid precursor cell line,
but transiently induced in a macrophage-like cell line or in
bone marrow-derived macrophages (9); (c) mouse neutrophils express all subtypes of A1, A1-a, A1-b, and A1-d (23); (d) although overexpression of Bcl-2 inhibits spontaneous
neutrophilic differentiation of a myeloid precursor cell line,
overexpression of A1 does not (18) (However, this does
not preclude the possibility that A1 is active in neutrophils.); and (e) furthermore, no enhancement of T cell
apoptosis was observed in A1-a
/
mice (Hatakeyama, S.,
unpublished results), which suggests a possible role for A1
in the restrictive lineage of hematopoietic cells.
Our present finding that A1-a/
mice exhibit enhanced
neutrophil apoptosis further strengthens the assumption
that A1 is a major suppressor of this process. Furthermore,
the finding that knockout of the A1-a subtype results in enhancement of neutrophil apoptosis suggests that this subtype functions as an important suppressor of apoptosis of
these cells. However, inasmuch as cycloheximide treatment
of neutrophils of wild-type mice induces greater apoptosis than that of A1-a
/
(Hamasaki, A., unpublished results),
the other subtypes, A1-b and A1-d, may also be involved
in neutrophil apoptosis inhibition.
It has been shown previously that treatment of neutrophils in vitro with cytokines such as IL-1 (26), G-CSF (26),
GM-CSF (26, 28, 29), and IFN- (26), which are detectable in inflammatory foci, inhibits apoptosis of these cells.
Furthermore, endothelial transmigration in vitro (30) and
in vivo (1) both delay neutrophil apoptosis. The present
finding that neutrophil apoptosis inhibition by LPS in vitro
and transendothelial migration in vivo were completely abrogated in A1-a
/
mice strongly suggests that A1-a is involved in this inflammation-mediated suppression of apoptosis.
The present finding that spontaneous neutrophil apoptosis is accelerated in A1-a/
mice (Fig. 4) suggests that
A1-a is also involved in this suppression of apoptosis. The
constitutive expression of A1 mRNA in neutrophils of untreated wild-type mice supports this assumption. As the
mechanisms involved in spontaneous neutrophil apoptosis,
autocrine death induced by Fas/FasL interaction on the
neutrophil surface (37), reactive oxygen intermediates (38,
39), and caspase (40), have been suggested as playing an active role in effector mechanisms, which may not necessarily
be mutually exclusive, and which may actually be interactive to some degree. An examination of candidate mechanisms and the manner in which A1 modulates apoptosis
will be the focus of future studies on A1 involvement in
spontaneous neutrophil apoptosis inhibition.
The finding in this study that inhibition of PEN and
LPS-treated PBN apoptosis was abrogated in both A1-a/
and A1-a+/
mice, whereas acceleration of spontaneous
PBN apoptosis was observed in A1-a
/
alone (Table 1),
may be explained as follows: in untreated PBN, the concentration of A1 protein in A1+/
may be sufficient to inhibit apoptosis, since mRNA expression of A1 in these
mice is 10-fold higher than in A1-a
/
, but only one tenth
that of wild-type 129Sv mice (Table 2). However, a greater
concentration of A1 protein may be required to inhibit
apoptosis of LPS-treated PBN or extravasated PEN, which may explain the lack of inhibition in A1-a
/
and A1-a+/
mice.
Our finding that TNF--induced acceleration of neutrophil apoptosis was not augmented in A1-a
/
is apparently inconsistent with the previous finding that transfection of the A1 gene into an endothelial cell line resulted in
inhibition of TNF-
-induced apoptosis of these cells (19).
This apparent discrepancy may be reconciled as follows:
first, although the discoveries of TNF receptor-binding cytoplasmic proteins such as TNF receptor 1-associated death
domain protein (41) and TNF receptor-associated factor
(42, 43) have expanded our understanding of the mechanisms of TNF-
-induced apoptosis, the picture is far from
clear. Various molecules such as IL-1
-converting enzyme-like protease (44), ceramide (45, 46), reactive oxygen intermediates (47), and nicotinamide dinucleotide (48)
have been proposed as candidates for mediators of TNF-
-
induced apoptosis. On the other hand, nitric oxide (49)
and A20 zinc finger protein (50) are both thought to be inhibitors of this form of apoptosis. Apoptosis induction and
inhibition through mechanisms involving the above molecules are dependent on cell type (44). Therefore, signal transductions governing TNF-
-induced apoptosis may
differ in neutrophils and endothelial cells. Secondly, a difference in the manner of TNF-
-induced apoptosis of the
two cell types may explain the discrepancy in the results,
i.e., why addition of actinomycin D is required for TNF-
-
induced apoptosis of endothelial cells (19) while TNF-
alone is sufficient to induce neutrophil apoptosis (1, 2). In
addition, our preliminary results suggesting that the GM-CSF-induced inhibition of neutrophil apoptosis was not
abolished in A1-a
/
mice (Hamasaki, A., unpublished results) themselves suggest that there exist systems of neutrophil apoptosis regulation other than those shown in this
manuscript.
The unexpected result that the number of PBN and
PEN was not significantly different in A1-a/
, A1-a+/
,
and wild-type mice may be explained as follows: (a) various systems other than A1, involved in the regulation of neutrophil apoptosis may compensate for this apoptosis in vivo;
(b) positive feedback regulation of PBN number may be induced in A1-a
/
mice through cytokines such as G-CSF;
and (c) a less probable possibility is that preapoptotic change
in cell surface carbohydrates which induce phagocytosis by
macrophages (51) may not differ between A1-a
/
, A1-a+/
, and wild-type mice and this may result in the same
grade of phagocytosis of preapoptotic neutrophils in these
strains of mice.
Studies are now in progress to more precisely elucidate the mechanisms of A1 involvement in the inhibition of neutrophil apoptosis and to examine whether A1 is also involved in the inhibition of apoptosis of myeloid cells other than neutrophils.
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Footnotes |
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Address correspondence to Fujiro Sendo, Department of Immunology and Parasitology, Yamagata University School of Medicine, 2-2-2 Iida Nishi, Yamagata 990-9585, Japan. Phone: 81-23-628-5263; Fax: 81-23-628-5267; E-mail: fsendo{at}med.id.yamagata-u.ac.jp
Received for publication 16 March 1998 and in revised form 28 September 1998.
This work was partially supported by a Grant-in-Aid for Scientific Research (09470069) from the Ministry of Education, Science, and Culture, Japan.We are grateful to Dr. Yuji Takeda, Akemi Araki, and Kazue Hayashi for technical assistance.
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