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ARTICLES |
in Hematopoietic Stem Cell Development and B Lymphocyte Maturation in the Male Mouse1
Department of Environmental Medicine, University of Rochester (T.S.T., F.G.M., T.A.G.), Rochester, New York 14642; Department of Microbiology and Immunology, State University of New York Health Science Center (J.E.S., A.E.S.), Syracuse, New York 13210; and National Institute of Environmental and Health Sciences (K.S.K.), Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Dr. Tom Gasiewicz, Department of Environmental Medicine, University of Rochester, 575 Elmwood Avenue, Box EHSC, Rochester, New York 14642. E-mail: Tom_Gasiewicz{at}urmc.rochester.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in hematopoietic
progenitor and B lymphocyte maturation. ER knockout
(ER-/-), wild-type (ER+/+), and
radiation chimeric (ER positive or negative in either
nonhematopoietic or hematopoietic elements, or both) male mice were
used to determine target tissues. ER-/- and
ER+/+ animals showed similar hematopoietic progenitor
profiles, but the ER-/- animals had fewer
cells in all bone marrow B lymphocyte subpopulations. Animals receiving
a pharmacological dose (5 mg/kg BW) of 17ß-estradiol (E2)
with both elements, ER+/+, had decreased early
hematopoietic progenitors and a shift toward a mature B cell
subpopulation, whereas animals with both elements,
ER-/-, showed changes only in early
hematopoietic progenitors. Hematopoietic element ER+/+
animals exhibited greater E2-induced hematopoietic
progenitor and B lymphocyte alterations than those having only
nonhematopoietic ER. These data indicate that 1) ER is not
necessary for regulating male mouse normal hematopoietic progenitor
cell proportions, but is involved in B cell regulation; and 2) ER in
hematopoietic elements is predominantly responsible for mediating
E2-induced hematopoietic and B cell changes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The presence of the estrogen receptor (ER) has been demonstrated in the
cells that constitute the immune system and in the various
nonhematopoietic elements that support their development. The prototype
ER, ER, has been detected in both thymic epithelial cells (11) and
thymocytes (11, 12), peripheral CD8+ T cells
(13), and bone marrow nonhematopoietic cells (14, 15) and B lymphocyte
precursors (15). A recently discovered ER isoform, ERß (16), has been
found in mouse bone marrow nonhematopoietic cells, male reproductive
tract, hypothalamus, and lung, usually in conjunction with ER (17, 18). ERß has also been demonstrated in rat bone, prostate, ovary,
lung, bladder, brain, uterus, and testis (19, 20) and in human thymus,
spleen, ovary, and testis (21). This isoform has been found at high
levels in the human thymus (21), but at low levels in the rat thymus
(20). The relative contributions of ER and ERß isoforms to
hematopoiesis and the reported estrogen-mediated changes in
hematopoiesis is unclear.
The importance of estrogens and ER in male mammals has only recently
begun to be fully appreciated. Several studies have shown a role for
the ER in normal growth and in the development and function of various
organ systems in both animal and human males (22, 23). Most studies
evaluating the effects of exogenous estrogens on the hematopoietic
process in animals have only incidentally reported on its effect in
males, and none has investigated their effect in the ER knockout
mouse model. Research from our laboratories has shown that thymuses of
the male ER knockout mice are smaller than those of their wild-type
littermates (24), indicating a function for ER in controlling immune
system development in these animals.
The present study was designed to evaluate the role of ER in
hematopoietic stem cells (HSC) and B lymphocyte maturation in
vehicle-treated and 17ß-estradiol (E2)-treated
bone marrow chimeras created using
ER-/- and
ER+/+ male mice. The use of chimeric mice allowed
us to investigate the in vivo effect of
E2 on the hematopoietic system in animals that
possessed ER in various combinations within their hematopoietic and
nonhematopoietic elements. The data derived using this model permitted
assessment of the relative importance of each element in mediating
E2-related hematopoietic alterations. Our data
show that ER is not essential for maintaining the normal proportion
of hematopoietic progenitor cell subsets in male mice, but it is
required for regulating the number of B cells reaching maturity. They
also show that a strong correlation exists between the presence of
ER in hematopoietic cells and alterations induced by high
pharmacological doses of E2 in HSC and pro/pre-B
and immature and mature B lymphocytes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Production of bone marrow chimeras
A complete discussion of the protocol used for production of
bone marrow chimeric mice can be found in the report by Staples
et al. (27). Briefly, 4-week-old Ly5.1 or Ly5.2
ER-/- mice were
irradiated twice with 550-rad doses, delivered 4 h apart. One
half-hour after the final irradiation the mice were administered 1
x 106 bone marrow cells from Ly5.1, Ly5.2
ER+/+, or Ly5.2
ER-/- mice by tail vein
injection. After reconstitution the mice were allowed to recover for 4
weeks before treatment to ensure full reconstitution of the thymus (28)
and release of mature cells of donor origin (29). This protocol has
been confirmed in our laboratory using CD45.1 (Ly5.1) and CD45.2
(Ly5.2) markers to assess thymic reconstitution (27), and
reconstitution of bone marrow B lymphocytes (<1% of total bone marrow
cells exhibited the host phenotype; data not shown). All chimera
designations in this paper will be shown with the donor mice on the
left and recipient mice on the right [i.e.
ER+/+
(donor)ER-/-
(recipient)].
Treatment protocol
Eight- to 9-week-old
ER-/-,
ER+/+, or ER chimeric mice received a single
sc injection of either 5 mg/kg BW of ß-estradiol 17-valerate
(Sigma, St. Louis, MO) in olive oil or olive oil alone
(0.1 ml/20 g BW). The E2 dose administered was
the minimum that produced a grossly verifiable effect upon the immune
system (i.e. >50% thymic atrophy) after 10 days (data not
shown). This end point was chosen to allow for assessment of changes to
thymic T cell subpopulations (24) in the same animals as those used in
the present study. Each experiment was performed using randomized,
age-matched animals (±3 days), with a minimum of four mice in each
treatment group (most chimeric experiments used five mice). All mice
were killed 10 days after treatment based upon data from our laboratory
showing that to be the time of maximum thymic atrophy after this
treatment (30).
Bone marrow cell isolation
Mice were killed by CO2 asphyxiation,
femurs and tibiae were removed, and the marrow cavities were flushed
with 10 ml Hanks’ MEM (Life Technologies, Inc./BRL, Grand
Island, NY) containing 5% FBS and penicillin-streptomycin (100 U/ml
penicillin and 0.1 mg/ml streptomycin; Life Technologies, Inc./BRL). The marrow cells were placed in suspension by
successive passage through 22- and 25-gauge needles and filtered
through 80-µm nylon mesh (TETKO Inc., Briarcliff Manor, NY) to remove
any remaining debris. The filtered cells were then pelleted by
centrifugation at 300 x g for 6 min. The pellet was
resuspended in 1 ml lysis buffer (0.17 M
NH4Cl, 10 mM
KHCO3, and 1 mM EDTA, pH
7.4) for 4 min to remove red blood cells. The cells were then washed
once and repelleted, and the pellet was resuspended in Hanks’ MEM to a
volume of 5 ml for cell counting. The cell yield was enumerated by
diluting the cells and counting at least two samples for each cell
preparation with a Neubauer hemocytometer (Hausser Scientific,
Horsham, PA). Cell viability was determined to be more than 90% by
trypan blue dye (0.08%) exclusion.
Antibodies
The following monoclonal antibodies were used at predetermined
saturating levels for labeling of B lymphocytes: fluorescein
isothiocyanate (FITC)-conjugated antimouse CD45R/B220 (B220; clone
RA3-6B2, rat IgG2a,
) and biotin-conjugated antimouse IgM (clone
R6-60.2, rat IgG2a). The monoclonal antibodies used at saturating
levels to label hematopoietic progenitor cells were biotin-conjugated
anti-TER119 (clone TER119, rat IgG2b), biotin-conjugated anti-B220
(clone RA3-6B2, rat IgG2a), biotin-conjugated anti-Gr-1 (clone RB6-8C5,
rat IgG2b), biotin-conjugated anti-Mac-1 (clone M1/70, rat
IgG2b), biotin-conjugated anti-CD3
(clone 500A2, hamster IgG),
biotin-conjugated anti-CD8 (clone 53-6.7, rat IgG2a),
FITC-conjugated anti-c-Kit (clone 2b8, rat IgG2b), and PE-conjugated
anti-Sca-1 (clone E13-161.7, rat IgG2a). All antibodies were obtained
from PharMingen (San Diego, CA).
Cell staining and flow cytometry analysis
Freshly isolated bone marrow cells from each mouse were pelleted
by centrifugation and washed in HBSS with Ca2+
and Mg2+ (Life Technologies, Inc./BRL) containing 0.2% BSA (HBSS-0.2% BSA). After the wash
step each pellet was resuspended in HBSS-0.2% BSA to a concentration
of 1 x 107 cells/ml. Aliquots of 1 x
106 cells (for B lymphocyte analyses) and 8
x 106 (for hematopoietic progenitor analyses)
were then preblocked with anti-Fc
III/IIR (clone 2.4G2, rat IgG2b; Fc
Block, PharMingen) for 15 min on ice to reduce nonspecific
binding.
The aliquots for B lineage staining were incubated with primary antibodies [FITC antimouse CD45R/B220 (B220) and biotin antimouse IgM] for 30 min on ice. After this procedure the cells were washed twice in HBSS-0.2% BSA, and the cells receiving treatment with the biotinylated antibody were incubated in streptavidin-Cy-Chrome (PharMingen) for 30 min on ice. After completion of staining, the cells were washed twice in HBSS-0.2% BSA and fixed in 1% paraformaldehyde (in Dulbecco’s PBS; Life Technologies, Inc./BRL). All samples were stored at 4 C and analyzed within 3 days after fixation.
The cell aliquots reserved for hematopoietic progenitor analyses were
incubated for 30 min on ice in a cocktail of biotin-conjugated
monoclonal antibodies (anti-Mac-1, anti-Gr-1, anti-Ter-119,
anti-CD3, anti-CD8, and anti-B220) diluted with HBSS-0.2% BSA.
Additionally, the cocktail contained PE-conjugated Sca-1 mAb and
FITC-conjugated c-Kit mAb. For these cells, the remaining wash steps,
streptavidin-Cy-Chrome incubation, and the fixation step were as
described above for the B lymphocyte lineage stains.
Data for the fixed bone marrow cells stained for the B lymphocyte
lineage were acquired on a Becton Dickinson and Co.
FACScan flow cytometer (Mountain View, CA) with BD Lysys II software
and analyzed using Becton Dickinson and Co. CellQuest
software (version 3.1). Fifty thousand events were acquired and
analyzed for each sample. Analyses were performed on the viable cell
population gate delineated by forward scatter vs. side
scatter parameters (Fig. 1
). This gate
was used to preclude the inclusion of cellular debris and dead cells in
the analyses. Analysis gate coordinates for each subpopulation were set
using vehicle-treated control bone marrow and maintained for all
animals analyzed in each experiment.
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).
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A simplified schematic of the HSC development and B lymphocyte
maturation pathways is shown in Fig. 3.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). However, E2
treatment caused a significant decrease in the number of cells in those
intact and chimeric animals having ER in either the hematopoietic
and nonhematopoietic compartments or in both (Table 1).
|
). There was,
however, a significant reduction of c-Kit+
Sca-1+ cells in ER+/+ and
ER-/- groups after
E2 treatment, with this change being more
pronounced in the ER+/+ mice (Table 2). In
addition, significant decreases in the percentage of
c-Kit- Sca-1- and
c-Kit+ Sca-1- subsets occurred
within the hematopoietic compartment of the
ER+/+, but not
ER-/-, mice (Table 2). A
significant decrease in the relative percentage of cells that were
lin- was seen in the
E2-treated ER+/+
group vs. the vehicle-treated group (Table 2).
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ER+/+ group (Table 3) produced shifts in c-Kit/Sca-1
phenotypes comparable to those seen in the ER+/+
nonmanipulated mice (Table 2
), i.e. significant reductions
in the c-Kit+Sca-1+,
c-Kit-Sca-, and
c-Kit+Sca-1- populations. Likewise,
a similar response to E2 treatment was
observed for these phenotypes in the
ER-/-ER-/-
(Table 3) group compared with the nonmanipulated
ER-/- animals (Table 2),
i.e. cells in the
c-Kit+Sca-1+ population
were significantly reduced. These findings show that hematopoietic
responses within the chimeras are similar to those occurring within the
nonmanipulated animals and serve to further validate our reconstitution
protocol.
|
ER+/+)
somewhat paralleled those of the
ER+/+ER+/+ chimeric
group, with statistically significant reductions in
c-Kit+ Sca-1+ and
c-Kit+ Sca-1- cells (Table 3). However, the magnitudes of these reductions in this chimeric group
were not as great as that observed in the
ER+/+ER+/+ chimeric
group.
In the chimeric group in which only hematopoietic elements contained
ER
(ER+/+ER-/-),
statistically significant decreases were seen within the
c-Kit+ sets as well as within the
c-Kit- Sca-1+ set (Table 3). The pattern and magnitude of phenotypic alterations were similar to
those seen after E2 treatment of the
ER+/+ mice and
ER+/+ER+/+ chimeric
mice. As was observed in the nonchimeric ER+/+
group, E2-treated
ER+/+ER+/+ animals had a
significantly decreased percentage of lin-
cells, whereas the E2-treated
ER-/-ER-/-
group percentage was not significantly different from that in the
vehicle-treated animals (Table 3). Additionally, the decreased
percentage of lin- cells that was seen in
E2-treated
ER+/+ER+/+ animals was
also observed in the
ER+/+ER-/-
mice. In contrast, the E2-treated
ER-/-ER+/+
and
ER-/-ER-/-
animals did not have a significant decline in their
lin- cells (Table 3). Therefore, the groups of
mice possessing ER+/+ hematopoietic elements had
significantly lower percentages of lin- cells
after E2 treatment compared with groups with
ER-/- hematopoietic
elements. Taken together, these data suggest that ER contained in
the hematopoietic cells, but not in the nonhematopoietic cells, is the
principal mediator of the effect of E2 on the
proportion of lin- cells present in bone marrow.
However, as indicated above, several E2-elicited
changes involving Sca-1/c-Kit alterations appear to be independent of
the presence of ER (Tables 2 and 3).
B Lymphocyte subpopulations in E2-treated
and vehicle-treated animals
Three previously described (36) B lymphocyte maturation stages
were analyzed based upon their level of membrane staining for B220 and
IgM antibodies: pro/pre-
(B220low)/IgM-), immature
(B220low/IgM+), and mature
(B220high/IgM+) B
lymphocytes (Fig. 1). We observed that the percentages of cells in the
three bone marrow B lymphocyte subpopulations (at the point at which
they were analyzed in our study, i.e. 5.5 weeks after
reconstitution) were comparable in all four vehicle-treated chimeric
groups and only marginally different from the values in the nonchimeric
vehicle-treated animals (data not shown). This provided some assurance
that B lymphocytes had stably reconstituted in all chimeric groups.
Comparison of B lymphocyte subpopulations in
ER+/+ and ER-/-groups, and the effect of E2 in these
animals
The cell counts in each B lymphocyte subpopulation in the
vehicle-treated ER-/-
group were significantly decreased vs. the comparable
subsets in the ER+/+ vehicle-treated group (Fig. 4A). E2 treatment
produced a decrease in the number of cells in the pro/pre- and immature
B subpopulations and an increase in the mature subpopulation cell
numbers for the ER+/+ group vs. the
vehicle-treated group, whereas no change was observed for any of the
subpopulations in the
ER-/- group (Fig. 4B).
|
ER-/-,
ER+/+ER-/-,
and
ER-/-ER+/+
groups differed significantly from those of the
ER+/+ER+/+ group.
However, although this subpopulation was decreased in the
ER-/-ER-/-
and
ER+/+ER-/-
animals, it was increased in the
ER-/-ER+/+
group (Fig. 5A). The only chimeric group
in which the immature and mature B subsets differed from those of
the ER+/+ER+/+ animals
was the
ER+/+ER-/-
group, where these subpopulations were slightly, but significantly,
reduced (Fig. 5A).
|
ER+/+
reconstitution groups (Fig. 5B) were similar to those seen in B cells
from the ER+/+ group (Fig. 4B).
E2 treatment of the
ER-/-ER-/-
animals produced no significant differences for any of the B cell
subpopulations (Fig. 5B). This similarity in response between the
chimeric and nonchimeric treated groups again provides validation for
our reconstitution protocol.
Reconstitution of ER-/-
animals with ER+/+ bone marrow
(ER+/+ER-/-)
produced results for the E2-treated B cell
subpopulations similar to those seen in the groups in which ER
was present in both elements (ER+/+,
ER+/+ER+/+). The
pro/pre-B and immature B cell numbers were significantly decreased by
E2 treatment, whereas the mature subpopulation
was significantly increased (Fig. 5B). When
ER-/- bone marrow was
used to reconstitute animals containing
ER+/+ nonhematopoietic cells
(ER-/-ER+/+),
E2 treatment produced a significant increase in
the immature and mature B cells (Fig. 5B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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null allele
chimeric mouse model in evaluating the role of this receptor in the
development of bone marrow hematopoietic progenitors and B lymphocytes.
By being able to generate animals containing ER in either the
hematopoietic or nonhematopoietic compartment or in both, we were able
to examine how its presence and absence in each compartment affects
normal hematopoiesis and B lymphopoiesis. This model has also allowed
us to observe the effects of E2/ER interaction
on these processes within each compartment.
The cell frequency data suggest that ER may have little or no role
in the generation and maintenance of hematopoietic progenitor cells,
although it may be involved in regulating B cell lineage commitment.
The chimeric data are consistent with a model in which the expression
of ER in the nonhematopoietic compartment is essential primarily for
the development of the most immature, i.e. pro/pre-B,
population of B cells, whereas the proportional expansion of the more
mature populations occurs independently of ER in either compartment.
It should be noted that thymuses from animals in those groups negative
for nonhematopoietic ER had significantly decreased total
cellularity vs. those possessing ER in this compartment
(24). Taken together, these results strongly suggest that
nonhematopoietic ER is necessary for both the maintenance of normal
numbers of bone marrow cells undergoing B lymphopoiesis and the support
of developing thymocytes.
Nonhematopoietic elements (e.g. epithelial cells,
macrophages, dendritic cells, etc.) are important in
regulation of early hematopoietic cell development through the release
of cytokines and other factors. Although our results show that ER
does play a role in this process, the exact mechanism of this
involvement is not known. It is possible, for example, that ER may
directly or indirectly regulate the production and/or secretion of
cytokines, e.g. interleukin-7 (IL-7), required for the
development of the early B lymphopoietic stages. Murine bone
marrow-derived stromal cell lines express ER, which apparently mediate
the release of several cytokines in response to
E2 treatment (14). Additional studies involving
other specific bone marrow cells (e.g. myeloid) in these
animals would determine whether ER also has a role in their
development and maturation or whether the effect is specific for the
lymphoid lineage.
Our data differ from the results reported by Smithson et al.
(18), who noted no difference in the occurrence of bone marrow
B220+/IgM- cells in male
ER-/- mice vs.
ER-positive mice. The reasons for the difference in our findings are
not readily apparent. However, Smithson’s group used the anti-CD45RA
antibody, which, when combined with the anti-IgM antibody, stained only
two subsets of B lymphocytes. We used the antibody for CD45R/B220 (36),
which, combined with IgM, delineated three B cell subsets.
We consistently observed a reduction in the total number of bone marrow
cells in the ER+/+ and
ER+/+ER+/+ animals after
E2 treatment. These data are consistent with
those presented by Medina and Kincade (37), who reported decreased
numbers of nucleated bone marrow cells recovered in
E2-treated mice. They also noted difficulty in
removing bone marrow from the E2-treated animals
due to an increase in cortical bone vs. hematopoietic
marrow, a problem that we also encountered in our
E2-treated ER+/+ and
ER+/+ER+/+ animals.
Estrogen administration to mice has been shown to produce up-regulation
of osteoblast activity and subsequent increased bone density and
decreased marrow volume (reviewed in Ref. 38). This may at least
partially explain the lower bone marrow cell counts from the
ER+/+ and
ER+/+ER+/+ animals.
Treatment of the ER-/-
and
ER-/-ER-/-
animals with E2 produced no significant decrease
in the bone marrow cell counts, consistent with ER involvement in
this change. The decreased total bone marrow counts in the
ER+/+ER-/-
and
ER-/-ER+/+
groups receiving E2 indicates that the presence
of ER in either compartment mediates the effect of
E2 on reducing total bone marrow cell numbers.
These findings suggest that cellular interaction between the two
compartments is necessary for maintenance of hematopoietic homeostasis;
however, additional research needs to be performed to further address
this.
The decrease in the c-Kit+Sca-1+ HSC in the male ER+/+ group after treatment with a pharmacological dose of E2 is in line with data from female rodents showing that estrogen supplementation reverses the increase in hematopoiesis after estrogen withdrawal (39). Likewise, the E2-related decreases we observed in the pro/pre-B and immature B subsets for this group are similar to that reported by Medina and Kincade (37) for the small pre-B cell subpopulation after E2 administration.
Although it does appear that ER deficiency is responsible for the
lack of effect of E2 on the B cell subpopulations
in the ER-/- and
ER-/-ER-/-
animals, the significant change observed in the
c-Kit+Sca-1+ HSC indicates
that non-ER pathways must be involved in the response of these early
progenitors. Other potential pathways regulated by estrogen could be
interaction with ERß or an ER messenger RNA (mRNA) splice variant
protein. Recent research has shown that ERß and the functional ER
mRNA splice variant ERKO-E1 occur in bone marrow nonhematopoietic cells
of ER-/- and
ER+/+ mice (18). Although the precise function of
the ERß receptor is not known, it exhibits an affinity for
E2 similar to that of ER (16). The
ER-/- splice variant has
been shown to produce a protein that has a similar affinity for
E2 as the full-length ER mRNA-produced
protein, although with decreased transcriptional activity (40). It is
also possible that estrogen may be acting via a nongenomic pathway.
Membrane estrogen-binding sites have been demonstrated in various
tissues (reviewed in Ref. 41), and Benten et al. (42) have
shown their presence on splenic T lymphocytes from female mice.
Although membrane ERs have not been reported on bone marrow
hematopoietic cells, this alternate pathway cannot be ruled out as a
potential route for estrogen action.
Taken together, these results show that a major determinant for the
in vivo responsiveness of HSC populations to
E2 treatment was the presence of ER in the
hematopoietic cells. Although the precise mechanism mediating these
changes is not known, the data suggest that the presence of ER in
the hematopoietic elements is necessary for an
E2-mediated blockade of the transition from less
mature (c-Kit+/Sca-1+) to
more mature (c-Kit+/Sca-
and c-Kit-/Sca-1-)
hematopoietic progenitors. This premise is supported by previous work
from our laboratories showing that E2
administration to female BALB/cJ mice produced a decrease in levels of
recombinase activating gene-1 mRNA in bone marrow cells (30). This
change was hypothesized as a mechanism for the thymic atrophy observed
in these animals.
E2 treatment resulted in an effect that suggests
an accelerated maturation of B cells from the less mature to the mature
stage. Analysis of the chimera data indicated that this was determined
primarily by the presence of ER in hematopoietic cells. This finding
contrasts with the in vitro work of Smithson et
al. (15), who showed that estrogen interaction with
nonhematopoietic cells grown under IL-7-supplemented culture conditions
was important in the estrogen-induced reduction of very early B cell
precursors. The difference between our results may be attributable to
our assessment of subpopulations made up of predominantly more mature B
cells, which are independent of nonhematopoietic cell and IL-7
regulation (43, 44). Further work using additional markers needs to be
performed to separate the pro/pre-B subpopulation into earlier
developmental stages [Hardy’s subfractions A–C (36)] to assess the
impact that the presence or absence of ER in the hematopoietic
and/or nonhematopoietic compartments has on these stages.
In summary, these data lead us to conclude that the presence of ER
in the nonhematopoietic compartment is necessary for the maintenance of
normal proportions of B lymphocytes in bone marrow, possibly by
mediating the production of the necessary growth factors and/or
cytokines. In contrast, exogenously administered
E2-associated alterations are mediated through
its interaction with ER-containing cells present predominantly, if
not exclusively, in the hematopoietic compartment. The effects of
E2 administration (at a concentration severalfold
greater than that required to restore uterine weights in ovariectomized
female mice) on the early hematopoietic cells may be a result of
involvement of a non-ER-mediated pathway or a compensatory response
to the E2-induced changes in the B lymphocyte
subpopulations. Additional research needs to be performed to evaluate
the role of ER in the production of factors, such as IL-7, by
nonhematopoietic elements in bone marrow, to assess other possible
non-ER pathways of E2 regulation of
hematopoiesis and B lymphopoiesis, and to establish a dose-response
relationship for the changes observed after elevation of the estrogen
level through, for example, exogenous estrogen treatment.
|
Footnotes |
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Received October 6, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(ER) and estrogen receptor-ß (ERß) messenger
ribonucleic acid in the wild-type and ER-knockout mouse.
Endocrinology 138:4613–4621 and ß. Endocrinology 138:863–870 is necessary in
thymic development and estradiol-induced thymic alterations. J
Immunol 163:4168–4174 L chain gene rearrangements and c-kit and IL-7
receptor expression in stromal cell-dependent pre-B cells. J
Immunol 149:1973–1979[Abstract]
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G.-J. Shim, L. L. Kis, M. Warner, and J.-A. Gustafsson Autoimmune glomerulonephritis with spontaneous formation of splenic germinal centers in mice lacking the estrogen receptor alpha gene PNAS, February 10, 2004; 101(6): 1720 - 1724. [Abstract] |
