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(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


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ABSTRACT
 
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
 
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.


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Restrictive role of mesenchymal stromal cells from bone marrow in regulation of hematopoiesis in vitro
 
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.


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Stromal activin A causes apoptotic death of myeloma cells
 
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, {alpha}/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 {alpha} 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
 
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.


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Involvement of activin A in inflammation and lessons from studies on nasal polyps
 
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 {alpha} 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.


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Concluding remarks on the updated restrictin model
 
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>

Received December 29, 2000; revised April 1, 2001; accepted April 5, 2001.


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