(Journal of Leukocyte Biology. 2001;69:867-873.)
© 2001
by Society for Leukocyte Biology
Role of activin A in negative regulation of normal and tumor B lymphocytes
Dov Zipori and
Mira Barda-Saad
Department of Molecular Cell Biology, the Weizmann Institute of Science, Rehovot, Israel
Correspondence: Dov Zipori, Ph.D., Department of Molecular Cell Biology, Rehovot 76100, Israel. E-mail:
dov.zipori{at}weizmann.ac.il
 |
ABSTRACT
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Activin A, a member of the transforming growth factor ß superfamily,
has a wide spread expression pattern and pleiotropic functions. In this
overview we summarize data that points to a role of activin A in
negative regulation of B lineage lymphocytes. Experiments performed by
us and by other groups revealed the capacity of activin A to cause
apoptotic death of tumor myeloma cells, through mechanisms of cell
cycle inhibition and antagonism with the survival signal of
interleukin-6. In vitro studies on B lymphocyte generation from bone
marrow stem cells and use of human nasal polyps as a model of inflamed
tissue further demonstrate an inhibitory role of activin A in B cell
spread and accumulation. These data are analyzed with respect to our
model of tissue organization that we term the "restrictin model of
cell growth regulation." This model assumes a morphogen-like role of
activin A in the hematopoietic system. Thus, the relative concentration
of biologically functional activin A, in different parts of the tissue,
may determine the local B cell content and functional state of these
cells within a specific microenvironment.
Key Words: signal transduction IL-6 restrictins myeloma
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INTRODUCTION
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Programmed cell death by apoptosis was described
[1
] long before it was accepted as the prevailing mode
by which development of multicellular systems is regulated. To date it
is known that defects in the apoptotic process are a hallmark of cancer
[2
]. Moreover, early in the emerging field of cellular
immunology, it was realized that the biology of the thymus entails
massive cell death and, in fact, that the vast majority of T
lymphocytes die within the thymus and never reach peripheral organs
[3
]. Nonetheless, this remarkably large-scale death
process, which later was realized to be of an apoptotic nature, was
regarded by immunologists as a specific property of the thymus. It is
now clear that B-lymphocyte generation is also associated with massive
elimination of cells during the differentiation process
[4
]. In 1988, we first proposed the "restrictin
model" of cell organization within hemopoietic organs
[5
]. This model was based on our studies of the
interactions between normal and leukemia cell lines and bone
marrow-derived mesenchymal stroma. Several experimental systems that we
used all pointed to a restrictive, rather than an inductive role of the
organ stroma in determining the cellular composition of tissues
[6
7
8
9
10
11
12
]. It was proposed that the organ stroma
elaborates regulatory molecules that restrain, inhibit, or actually
kill "unwanted" cells in an apoptotic manner. Although cytokines
that amplify differentiation processes had been isolated, by that time,
their pleiotropicity and lack of lineage specificity implied that
inductive microenvironments could not, by themselves, account for the
creation of specific domains within tissues, which contain a single
cell type or a single lineage. For example, the thymus is dominated by
T lymphocytes despite the fact that it is populated by multipotent bone
marrow stem cells capable of differentiating into all hemopoietic
lineages and despite the fact that stromal cells and T cells produce
cytokines that could, in principle, induce differentiation within the
thymus of many cell types other than T cells. Indeed, disruption of the
thymus and seeding of thymocytes in vitro onto bone marrow stromal
cells resulted in a burst of macrophage production or, in other
circumstances, in a wave of B-cell proliferation [13
,
14
]. Recent studies substantiate the presence of
B-lymphocyte populations within the thymus [15
]. Thus,
the thymic environment exerts a restrictive effect on cell types other
than T cells.
It is most illuminating that, thus far, not a single organ-specific
cytokine has been described and that it is not even possible to clearly
delineate a series of cytokines that would characterize one organ
versus another. It appears though that specific microenvironments
within tissues may differ in the profile of cytokines that predominate
within them. The local concentration of a given cytokine, relative to
others present in the specific site, may contribute to the creation of
a unique microenvironment. However, we propose that it is the task of
restrictive molecules to determine organ specificity and to protect
tissue integrity by complementing the lack of target cell specificity
of cytokines and by blocking the invasion and accumulation of
misplaced, unwanted cells. Tumor cell metastasis is one example of such
undesirable cells that may invade and damage tissues. These cells are
rare, however, compared with hemopoietic cells that constantly travel
and reach distant sites in the organism. Hemopoietic cells are
therefore a constant threat to tissue integrity and must be stopped
before invading or eliminated by apoptosis after invasion. The
situation is even more dramatic within the hemopoietic
microenvironment. To maintain the specific architecture, such as the
red versus white pulp of the spleen or the erythroid islands of the
bone marrow, in these highly dynamic organs, a mechanism that represses
or even kills unwanted cells should be operating. When first published
and presented, this view was criticized on grounds that cell death is
rare in the marrow or other nonhemopoietic organs and tissues. The huge
advance in the field of apoptosis and the availability of tools to
study cell death made it clear that tissue organization and modeling,
as well as development, entail cell death. The identification of adult
stem cells such as mesenchymal stem cells within the bone marrow that
are capable of differentiating into bone, muscle, cartilage, and fat
[16
, 17
]; cardiomyocytes
[18
]; and bone marrow-derived cells with a
differentiation potential towards epithelial hepatic oval cells
[19
] just intensifies the problematic issue of the
inductive view of tissue organization. It is obvious that a very strict
negative control should keep these multipotent tissue stem cells
quiescent; otherwise, tissues would become teratomalike chaotic
structures.
Our view on the regulation of tissue organization has been extensively
reviewed in the past [20
21
22
23
24
25
26
27
]. This manuscript presents
a modified version of the restrictin model of tissue organization,
based on the identification of several stromal molecules that control
the B-lymphocyte lineage.
 |
Restrictive role of mesenchymal stromal cells from bone marrow in
regulation of hematopoiesis in vitro
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Hemopoiesis in long-term bone marrow cultures is
dependent on the support of mesenchymal stromal cells. It has been
proposed that this dependence results from production by the stroma of
cytokines endowed with growth- and differentiation-inducing activities.
However, although over two decades have passed since the Dexter
long-term bone marrow culture system was established
[28
], the minimal molecular requirements that underlie
this biological phenomenon have not been defined. Specifically, it is
still unclear which molecular signals direct hemopoietic stem cell
(HSC) maintenance and proliferation in vitro or their renewal in vivo.
On grounds of quantitative studies using cocultures of bone marrow
cells seeded onto stromal cell layers [29
], we proposed
that the renewal of stem cells is secondary to differentiation
restraint imposed by stromal cells. We further proposed that this
effect is mediated by antagonists of differentiation processes produced
by the mesenchymal stroma. In addition, we specifically indicated
transforming growth factor (TGF)-ß as one part of this regulatory
process that protects stem cells from differentiation
[23
]. This last notion gained support from later studies
that were recently reviewed [30
]. Other molecules that
may take part in this process were suggested to be lineage and
cell-type specific "restrictins." This suggestion was deduced from
a study on the interactions between leukemia cell lines and bone marrow
stromal cells, which found that among a series of leukemia cell lines
including T and B lymphomas; myeloid, macrophage, and erythroid tumors;
and plasmacytomas, only the latter were strongly growth inhibited when
cultured onto bone marrow-derived stromal cells. These experiments
showed that the bone marrow stroma harbors a molecule(s) that
specifically inhibits one cell type while sparing others. We therefore
designated this stromal activity as restrictin-P to denote the ability
of the putative factor to specifically restrict the growth of
plasmacytomas. A search for the stromal molecule that mediates this
cell-type-specific growth inhibition culminated in purification of the
factor from the bone marrow-derived stromal cell line MBA-2.1. The
isolated protein was identified as being activin A, a member of the
TGF-ß superfamily [31
, 32
]. We recently
found that activin A suppresses in vivo the development of plasmacytoma
tumors in a nude mouse model [33
]. The development of
these tumors is dependent on stromal cell support, a phenomenon that is
reminiscent of the dependence of multiple myeloma cells on the bone
marrow stroma microenvironment. The expression of activin A by stromal
cells could be enhanced by basic fibroblast growth factor, rendering
the stroma suppressive to myeloma cells. We propose that the local
relative concentrations of these regulators within the bone marrow
might determine the emergence of multiple myeloma.
 |
Stromal activin A causes apoptotic death of myeloma cells
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Activin A is a pleiotropic molecule involved in a plethora of
biological activities. It is a 25-kDa homodimer of the ßA chain of
inhibin and has been extensively studied as a component of the hormonal
network that regulates the function of the reproductive system in
mammalians [34
, 35
]. Activin A is found in
the peripheral blood stream and controls follicular stimulating hormone
secretion from the anterior pituitary gland. This classical
hormone-like function is regulated by several negative-control
molecules including follistatin [36
, 37
]
and inhibin A, which are activin A-binding or activin receptor binding
protein, respectively. Inhibin A itself is a member of the TGF-ß
superfamily and is a heterodimeric protein,
/ßA. Thus, activin A
and this particular inhibitor of its function share a subunit
component. This provides an additional level of control on the
expression level rather than the functional level; when the relative
amount of the ßA chain synthesized by a given cell exceeds that of
chain, activin A rather than its inhibitor is the major cellular
product.
The mode by which activin A causes growth inhibition of plasmacytoma is
apoptosis [32
, 38
]. The death of
plasmacytoma cells is probably a result of two separate effects of the
molecule. One effect is its inhibition of cell cycling. Activin A
caused reduced expression of the cyclin-dependent kinase
(CDK)4 and a concomitant increase in the CDK inhibitor
p21Waf1/Cip1 due, in part, to increased transcription of
the encoding gene [39
]. These findings performed in a
human hepatoma cell model have been further substantiated by studies on
B-lineage cells [40
]. It is noteworthy that hepatoma
cells are growth inhibited by activin A but do not die. Thus, the cell
cycle arrest does not necessarily lead to apoptotic death. We found
that activin A is a competitive antagonist of interleukin (IL)-6
[31
, 32
], which is a growth factor for
mouse and human myeloma cells. Activin A binds to specific receptors on
mouse plasmacytoma cells and elicits an intracellular signaling cascade
that interferes with IL-6 signaling and thus deprives plasmacytoma
cells of their growth signal. Our recent studies showed that this
effect is mediated by the intracellular mediators of activin A
functions, i.e., Smad2, Smad3, and Smad4 proteins that block the
transcription of IL-6 inducible genes, as is schematically
shown in Figure 1
[40a
].

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Figure 1. A schematic view of the signaling pathways of IL-6 and activin A: The
left-hand side of the scheme shows the IL-6 receptor complex that on
ligand binding activates the Jak/STAT and MAPK pathways, leading to
binding of the corresponding transcription factors, STATs and NF-IL6
(C/EBPß), to promoter sites in IL-6-inducible genes. Our study
indicates that the activation of transcription from one such
IL-6-inducible gene, the acute-phase protein haptoglobin gene, is
blocked by activin A. The right-hand side of the scheme shows the
activin A signaling cascade. Engagement of activin A receptor by the
ligand causes activation of the intracellular mediators, Smads. The
receptor Smads (Smad2 and Smad3) form homodimers and then
heterodimerize with the co-Smad4. The formation of this complex leads
to translocation into the nucleus. We found that Smad proteins
interfere with the transcriptional activation of IL-6 genes on the
level of STAT-3 and C/EBPß (indicated in the scheme by the X sign on
the line connecting the activin and IL-6 signaling
cascades)._art>
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 |
Activin A negatively regulates B-lymphocyte generation
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One of the acronyms of activin A is erythroid differentiation
factor (EDF). It was found that cell supernatants could cause
differentiation of erythroleukemia cell lines by the presence of a
molecule that, on purification, turned out to be activin A. In fact,
this biological activity was the first of the functions of activin A to
be described that relates to the hemopoietic system [41
,
42
]. Several studies have shown that activin A affects
normal erythroid cells via an indirect mechanism, through activation of
cytokine secretion by macrophages, T cells, and stromal cells
[43
44
45
46
]. Activin A mRNA has been detected within the
bone marrow stromal compartment [47
] and is expressed by
cultured stromal cell lines and clones that we derived from mouse bone
marrow [12
, 31
]. It is of interest that the
MBA-2.1 stromal cell clone, which has an endothelial phenotype,
expresses high activin A titers and, in fact, has been used for the
purification of activin A in our laboratory [31
]. Other
cell lines that we obtained have mesenchymal properties. These produce
activin A at a lower titer compared with the endothelial clone
[12
, 32
]. This low expression of activin A
in cultured mesenchymal stromal cells is increased after treatment with
basic fibroblast growth factor [48
]. A recent study
performed in our laboratory using long-term lymphopoietic bone marrow
cultures indicated that the production of pre-B cells is dependent on
the relative amount of functional activin A expressed in these
cultures. Thus, elevated expression of activin A in primary bone marrow
cultures is associated with lack of development of lymphopoiesis.
Addition of the activin A inhibitor follistatin enhances pre-B-cell
production [T. Shoham, R. Parameswaran, D. Zipori, unpublished
results]. This study further showed that the ability of stromal cells
to produce biologically functional activin A depends on the relative
amount of activin versus inhibin and follistatin produced. For example,
cells in which the production of follistatin predominates are not
inhibitory to plasmacytoma cells despite the expression of activin A.
Immunohistochemical analysis further suggests compartmentalized
expression of activin A within hemopoietic organs. However, it is still
unclear whether activin A is functional in vivo within the hemopoietic
microenvironment, as a regulator of B-cell growth, and further studies
are required to resolve this issue.
 |
Involvement of activin A in inflammation and lessons from studies
on nasal polyps
|
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Nasal polyps are swellings of the lamina propria mucosa, a
condition that is treated by surgical removal. Chronic infection,
allergy, asthma, and cystic fibrosis have been shown to be associated
with increased incidence of polyposis [49
]. The
infiltrating cells in nasal polyps are mainly eosinophils, mast cells,
neutrophils, T and B lymphocytes, and plasma cells. Several cytokines
also have been shown to be present in polyps and have been implicated
in the pathogenesis of nasal polyps [50
51
52
53
54
55
56
57
58
59
60
]. The
migration of blood-borne cells into the developing polyp is probably
controlled by chemokines such as IL-8 [58
] and RANTES
("regulated on activation, normal T expressed and secreted")
[60
]. The proliferation, survival, and functioning of
infiltrating cells may be regulated by molecules such as IL-3
[61
], granulocyte macrophage-colony stimulating factor
(-CSF) [50
], and vascular endothelial growth factor
[62
], all of which have been detected in polyp tissues.
IL-5 has been shown to be expressed by eosinophils and to induce their
growth, probably in an autocrine manner [61
]. TGF-ß1,
TGF-ß2, and TGF-ß3 have been proposed to stimulate deposition of
extracellular matrix proteins in the growing polyp
[53
54
55
, 59
]. Our recent studies showed
that activin A is detectable by immunostaining, primarily in the
epithelial component of the polyp and also in the mesenchymal stroma. A
major problem in identification of activin A protein by both reverse
transcriptase-PCR and immunodetection assays is that it is a dimer of
the ßA chain. The latter chain is shared by inhibin A.
Positive results in PCR or immunostaining with primers or antibodies to
ßA chain may indicate the presence in tissue of either activin A,
inhibin A, or a mixture of both. However, by reverse transcriptase-PCR
and immunostaining, we could not find evidence for expression of a
significant amount of the
chain of inhibin, and it was therefore
concluded that our data provide evidence for abundant expression of
activin A within human polyps.
The expression of activin A within the polyp was not uniform; we
noticed that immunohistochemical staining for ßA chain was
significantly reduced in domains within the polyp that were rich in
infiltrating B lymphocytes. We speculate that B cells may elaborate
molecules that suppress activin A expression. Conversely, lack of
activin A expression may create a permissive microenvironment that
allows the accumulation of B cells.
The finding that activin A expression in nasal polyps is
compartmentalized fits well with our expectation that activin A is
involved in tissue patterning. In invertebrates, TGF-ß superfamily
molecules serve as morphogens [63
]. The activin A
gradient has a major role in Xenopus development
[64
, 65
]. Although activin A has not been
shown to directly act as a morphogen in vertebrates, there is ample
indirect evidence that activin receptors have a determining role in
development and pattern formation [66
67
68
]. We therefore
propose that differential expression of members of the TGF-ß
superfamily within hemopoietic tissues contributes to pattern formation
due to the capacity of these molecules to inhibit cell growth and other
cellular processes.
 |
Concluding remarks on the updated restrictin model
|
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Figure 2
shows our current model of tissue organization. It is now clear
that at least some of the restrictive elements that operate within
microenvironments are cytokine antagonists. As we learned from stromal
activin A, a very complex system of regulators maintains the steady
state. Thus, the stroma produces activin A, which is a suppressor of B
cells and may cause reduced generation, growth inhibition, or actual
apoptotic death. At the same time, stromal cells elaborate other
molecules which in turn regulate the functions of activin A. Thus,
inhibin A and follistatin are both activin-binding proteins and inhibit
the ability of activin to bind to surface receptors and mediate their
biological functions. Whether the specific stromal cell or site within
a microenvironment is restrictive or inductive to B-lineage cells
depends on the relative proportion of expression of activin A versus
its inhibitors. The right-side sequence in Figure 2
shows a situation
in which the stroma produces an excess of activin A over its
inhibitors. This results in elimination of cells bearing activin A
receptors and in accumulation of cells that do not respond to activin.
The middle sequence shows the opposite situation, in which activin
inhibitors predominate and, in the absence of inhibitors for other cell
types, the stroma is permissive to all cells seeding on it. Finally,
the sequence on the left side of Figure 2
shows the generalized
conclusion, i.e., that there may be many restrictive molecules other
than activin A (denoted as X), within the TGFß superfamily and in
other gene families that operate in the same manner. Our views are
substantiated by recent studies that identified "limitin"
[69
], which preferentially kills B lymphocytes, and
WECHE [70
], which inhibits erythroid cells but has no
effect on myeloid cells or B lymphocytes. The molecular mode by which
these molecules operate seems to entail, at least partially, antagonism
to cytokine action. Thus, activin A is an antagonist of IL-6, IL-11,
and other cytokines within the IL-6 family, while other molecules are
known to antagonize yet other types of cytokines. This antagonistic
effect may lead to several consequences depending on the role that the
cytokine plays in the biology of the cells. If the cytokine is a
survival factor, the end result of the antagonist action will be death.
However, it should be realized that in situ cells are always exposed to
a plethora of signals rather than to a single cytokine. Therefore it is
likely that actual death occurs less frequently than under in vitro
isolated conditions and that, more often, the outcome is the halting of
growth or quiescence.

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Figure 2. The restrictin model of cell organization within tissues. Cell death by
apoptosis or, alternatively, halting of cell growth, is a major
mechanism for maintaining tissue integrity. Thus, particular stromal
cells express activin A, which is an antagonist of IL-6, and would
therefore prevent the accumulation of IL-6-dependent cells in their
proximity (right-hand sequence in the scheme). Other stromal cells that
express an excess of inhibitors of activin A (such as inhibin A) would
not interfere with the growth of IL-6-dependent cells or other cells,
provided that the microenvironment presents sufficient amounts of
survival cytokines (middle sequence). This private case can be extended
to any cytokine/antagonist combination (left-hand sequences). In
addition, cell killing or cell growth arrest may be mediated by other
molecules through mechanisms that do not include antagonism with
cytokine functions._art>
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Received December 29, 2000;
revised April 1, 2001;
accepted April 5, 2001.
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