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1. Reduced expression of activin A in focal lymphoid agglomerates within nasal polyps.
Shoham T, Yaniv E, Koren R, Gal R, Parameswaran R, Kravitz A, Geron H, Markovitz D, Lantzki M, Zipori D.
J Histochem Cytochem. 2001, 49:1245-52
It has been previously reported that activin A, a homodimer of the betaA inhibin subunit, is secreted by stromal cells from mouse bone marrow and causes apoptotic death of mouse plasmacytoma tumor cells. Recent in vitro studies have also implicated this cytokine in the suppression of normal B-cell lymphopoiesis. In this study we examined the occurrence of activin A in nasal polyp tissues that present a combination of epithelium, mesenchyme, and vascular endothelium, with frequent massive hemopoietic infiltration. Anti-betaA-chain antibodies strongly stained epithelial mucous glands and some endothelial cells, and diffusely stained the polyp stroma. Normal adult conchae were similarly stained, whereas activin A was not detected prenatally by immunostaining of nasal tissues. Staining specificity was substantiated by ligand competition assays. Detailed examination of the inflammatory polyp infiltrate showed that activin A staining was reduced in sites of focal infiltration of B-lymphoid cells. It is therefore implied that local accumulation of a large number of B-cells is associated with relatively low activin A expression.
2. The promotion of plasmacytoma tumor growth by mesenchymal stroma is antagonized by basic fibroblast growth factor induced activin A.
Shoham T, Sternberg D, Brosh N, Krupsky M, Barda-Saad M, Zipori D.
Leukemia 2001, 15:1102-10
The mesenchymal stroma has been shown to play a crucial role in the development of multiple myeloma, partly by secretion of interleukin (IL)-6, that serves as a growth factor for myeloma cells. However, it is still unclear which other stromal molecules are involved in the pathogenesis of this disease. We chose, as a model system, a mouse plasmacytoma cell line, which does not respond to IL-6. We found that the formation of mouse plasmacytoma tumors, in an in vivo skin transplantation model, is facilitated by co-injection of these tumor cells along with a mesenchymal stromal cell. The tumor promoting effect of the stroma was reproduced in an in vitro model; stromal cells induced the proliferation of plasmacytoma cells under serum-free conditions. This growth promotion could not be mimicked by a series of cytokines including IL-6 and insulin-like growth factor (IGF)-I implying a role for yet unidentified stromal factors. The in vivo formation of plasmacytoma tumors was reduced following administration of activin A, a cytokine member of the transforming growth factor (TGF)beta superfamily. Furthermore,
Zauberman A, Lapter S, Zipori D.;
J Biol Chem. 2001, 276:24719-25
Activin A, a member of the transforming growth factor beta (TGFbeta) superfamily, blocks interleukin (IL)-6 biological functions. The molecular basis of the influence of this TGFbeta signaling on the IL-6 receptor triggered cascade is unknown. We studied IL-6-induced secretion of the acute phase protein haptoglobin by hepatoma cells. Overexpression of the C/EBPbeta gene, a downstream effector in the IL-6 pathway, activated transcription from the haptoglobin promoter. This was abolished by either a constitutively active form of activin A type IB receptor (CAactRIB) or by a combination of Smad3 and Smad4. Similarly, Smads abolished transcriptional activation by co-stimulation with IL-6 and STAT3. The transcription co-activator p300 partially overcame the suppressive effect of Smads. Electrophoretic mobility shift assays indicated that C/EBPbeta binding to haptoglobin promoter DNA was reduced by over-expression of CAactRIB and Smad4. We thus show that Smad proteins operate as transcription inhibitors on target genes of the IL-6 induced pathway. The effect of Smads is exerted on components of the transcription activation complex and may also involve interference with DNA binding. This study thus depicts molecular sites of interaction between the TGFbeta superfamily and the IL-6 signaling cascades.Shoham T, Parameswaran R, Shav-Tal Y, Barda-Saad M, Zipori D.;
Ann N Y Acad Sci. 2003 May;996:245-60
The negative control of B cell generation is only partially resolved. We assessed the role of activin A in regulation of B lymphopoiesis in view of its specific inhibitory effects on tumor B lineage cells. Activin A is constitutively expressed in mouse hemopoietic organs and in cultured mesenchymal cell lines. We observed an inverse relationship between activin A titer and B lineage cell production. In the spleen, the red pulp exhibited a relatively higher abundance of the protein as compared with the lymphoid follicles, wherein B cell accumulation occurs. Furthermore, a specific shut off in activin A expression was observed in bone marrow and spleen following in vivo induction of B lymphocyte polyclonal activation. We further substantiated these in vivo observations by in vitro studies of primary bone marrow cultures, in which the expression of functional activin A was found to be diminished prior to the onset of B lymphopoiesis. The reduction in functional activin A is shown to concomitantly occur with spontaneous induction of the expression of activin A specific inhibitors. We therefore propose that the mesenchymal organ stroma expresses activin A that negatively controls B cell lymphopoiesis.Evron S, Parameswaran R, Zipori D, Ezri T, Sadan O, Koren R.
J Clin Anast. 2007 May;19(3):168-174.
STUDY OBJECTIVE: To investigate the immunohistochemical localization of betaA subunit of activin A in human term placenta, as a marker for placental infection/inflammation and elevated temperature, in parturients laboring during two analgesic regimens. DESIGN: Prospective, randomized controlled study. SETTING: Delivery room. PATIENTS: 56 healthy, ASA physical status I and II primiparous women in labor. INTERVENTIONS: Parturients were assigned to receive patient-controlled epidural analgesia (PCEA) with 0.2% ropivacaine or patient-controlled intravenous analgesia PCA with meperidine. MEASUREMENTS: Histologic and immunohistochemical placental evaluation for white blood cell infiltration and activin betaA staining were made. Maternal temperature elevation above 37.6 degrees C and leukocytosis above 15000/muL were recorded. MAIN RESULTS: Temperature was not significantly increased in parturients receiving PCEA over those who received (PCA) with meperidine (31% vs 11%, respectively; P = 0.1). There was also no association between temperature elevation during epidural analgesia and increased white blood cell count (>15000/muL) or presence of polymorphonuclear and/or lymphocyte aggregation in the placenta. Immunohistochemical staining with antisera against the betaA subunit of activin was present mainly in the placental cytotrophoblast, syncytiotrophoblast, and vascular endothelium, and was not associated with an increase in maternal temperature. No significant difference was noted between the two analgesic techniques with regard to maternal temperature elevation. Intrapartum temperature elevation was not associated with histologic signs of placental inflammation or with expression of activin betaA in the placenta. CONCLUSION: Other mechanisms may be involved in the etiology of temperature elevation during labor.Reshmi Parameswaran, Vered Morad, Ayelet Laronne, Liat Rousso-Noori, Nir Shani, Suha Naffar-Abu-amara and Dov Zipori
Stem Cells and Development. 2008 Feb;17(1):93-106
In vitro and in vivo studies implicate a series of cytokines in regulation of lympho-hemopoiesis. However, direct indications for a local role of most of these cytokines, within the bone marrow, is lacking. In the present study we aimed to test the contribution of a specific cytokine, activin A, a member of the transforming growth factor (TGF)beta family, to lympho-hemopoiesis in mouse bone marrow. We show that mouse embryo fibroblasts (MEF) are indistinguishable from multipotent stromal cells (MSC). Such MEF overexpressing activin A, supported in vitro myelopoiesis, in long-term bone marrow cultures, as effectively as control MEF. In contrast, activin A overexpressing MEF interfered with the in vitro generation of B lineage cells in such cultures. Thus, excessive expression in vitro of activin A by supportive stromal cells causes preferential maturation of myeloid rather than lymphoid cells. Moreover, the activin A overexpressing MEF caused in vivo an increased incidence of relatively immature B lineage cells; upon transplantation through the spleen route MEF engrafted the bone marrow specifically. Activin A overexpressing MEF accumulated in the bone marrow compartment and slowed down the progression of B cell precursors along the differentiation pathway, while sparing the myeloid population. The assay system described herein therefore provides a means to assess the contribution of a wide range of molecules to hemopoiesis without perturbing the constitution of other organs. Mechanisms may be involved in the etiology of temperature elevation during labor.
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