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PubMed1988

Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity.

Antigen-independent cell lines were derived from mouse helper T-cell clones by culture in autologous supernatant obtained after stimulation with concanavalin A. A factor, termed P40, supporting the growth of these lines was purified and characterized as a basic 32- to 39-kDa single-chain glycoprotein functionally distinct from previously identified T-cell growth factors and apparently unrelated structurally to any known protein. Of a number of cell lines, only helper T cells responded to P40, and this response was not mediated by either interleukin 2 or interleukin 4.

Amino Acid Sequence↗
PubMed1989

Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40).

Recently, we described a murine helper T cell-derived molecule with T cell growth factor activity that is functionally and structurally distinct from IL-2, IL-4, and other known growth factors. This molecule, designated P40, was identified as a glycoprotein capable of supporting antigen-independent growth of certain helper T cell clones. Here, we report the cloning and expression of a cDNA for this new growth factor. The predicted mature protein is a cationic cysteine-rich polypeptide of 14 kD without significant homology to previously sequenced proteins.

Amino Acid Sequence↗
PubMed1991

Autonomous growth and tumorigenicity induced by P40/interleukin 9 cDNA transfection of a mouse P40-dependent T cell line.

To test the transforming potential of deregulated P40/Interleukin 9 expression, we transfected a mouse P40-dependent T cell line with P40 cDNA, and examined the tumorigenicity of the resulting transfectants. When the cells, which grew autonomously in vitro, were injected intraperitoneally or subcutaneously into syngeneic mice, a very high tumor incidence was observed with as few as 10(4) cells per inoculum. Animals died as a result of widespread dissemination of lymphomatous tissue to abdominal and thoracic organs. The same P40-dependent cell line transfected with a control construct did not form tumors even after injection of 10(7) cells. These results indicate that uncontrolled expression of P40 can support T cell proliferation in vivo, and may be a transforming event involved in the development of certain T cell tumors.

Animals↗
PubMed1992

Activation of cytokines in Hodgkin's disease.

The complex histological pattern in Hodgkin's disease and in part in large cell anaplastic lymphomas (ALCL) suggests that close interactions exist between the tumor cells and reactive bystander cells. These interactions are most likely mediated by short ranged cytokines. The production of cytokines was analyzed in primary tissues and cell lines from Hodgkin's disease and ALCL by enzyme linked immunosorbent tests (ELISA), Northern blotting, immunohistological staining and in situ hybridization experiments. Our results indicate that Hodgkin's disease derived cell lines produce a variety of cytokines, such as IL1 alpha, IL4, IL5, IL6, IL8, IL9, TNF alpha and TNF beta but not IL1 beta, IL2, IL3 and G-CSF. In addition, the receptors for IL6 were detected in some of the cell lines. The expression of IL6 and IL6 receptors and IL9 has been confirmed for some primary tissues of Hodgkin's disease. From our data, we conclude that IL6, IL9 and additional cytokines are involved in the biology of Hodgkin's disease and ALCL.

Cell Line↗
PubMed1989

Complete amino acid sequence of a new murine T-cell growth factor P40.

A new murine T-cell growth factor, designated P40, which supports growth of helper T-cells in the absence of interleukin-2, interleukin-4 and antigen has been isolated from helper T-cell lines in sufficient quantities (100 micrograms) to permit its complete amino acid sequence determination. This was achieved by a combination of sensitive peptide mapping using microbore reversed-phase high performance liquid chromatography and automated microsequence analysis. Attempts to obtain N-terminal sequence data on P40 were unsuccessful due to N-terminal blockage of the native molecule. The nature of this N-terminal blocking was established using a combination of amino acid analysis, fast-atom-bombardment mass spectrometry and peptide synthesis. The P40 molecule, a single polypeptide chain comprising 126 amino acid residues, is structurally distinct from other known T-cell growth factors. No similarity was revealed when the amino acid sequence of P40 was compared with other proteins whose biochemical structure is known. The protein sequence data reported here predict four N-linked glycosylation sites in the P40 molecule.

Amino Acid Sequence↗
PubMed1992

[Cytokines and malignant lymphomas].

Cytokines are potent modulators of the physiological immune response. A number of reactive processes are associated with a deregulation of this cytokine expression. Animal models with transgenic mice or transfection experiments have shown that an autocrine or paracrine pathway might be involved in tumor progression and/or tumorigenesis. The study of cytokine expression in malignant lymphomas showed a heterogeneous expression pattern with a number of cases which quantitatively show indications for a marked deregulation of the cytokine expression. The expression od IL-7 and IL-9 seem to be special features of Hodgkin's disease and large cell anaplastic lymphomas. Transfection experiment with IL-9 into mouse T cells results in an autocrine loop and tumorigenesis of the transfected cells. These tumors share a number of similarities to Hodgkin's disease and large cell anaplastic lymphomas in human.

Animals↗
PubMed1992

Human interleukin (IL)-9 specifically stimulates proliferation of CD34+++DR+CD33- erythroid progenitors in normal human bone marrow in the absence of serum.

The cDNA encoding human interleukin (IL)-9 has recently been cloned and the recombinant molecule found to enhance erythroid colony formation in vitro by bone marrow, peripheral blood, and cord blood cells. In our present report, recombinant human (rhu) IL-9 was evaluated, alone and in combination with other cytokines, for its effect on colony formation by erythroid progenitor (erythroid burst-forming units, BFU-E) and precursor (erythroid colony-forming units, CFU-E) cells in low density (LD), nonadherent LD density T-lymphocyte-depleted (NALT-), and immunofluorescence-sorted CD34+++DR+ and CD34+++DR+CD33- cells from normal human bone marrow. When highly enriched CD34+++DR+ and CD34+++DR+CD33- cells were plated at 200 and 100 cells/ml in the presence of 5% (vol/vol) 5637-cell-conditioned medium and erythropoietin (Epo) under serum-containing conditions, 46 and 51 day-14 BFU-E were observed, respectively. The enhancing effect of rhuIL-9 was similar to that of 5637 CM on colony formation by Epo-dependent BFU-E and CFU-E in these enriched sorted CD34+++DR+ and CD34+++DR+CD33- cells under serum-containing and serum-depleted culture conditions. No significant synergistic or additive effect of rhuIL-9 was noted when used in conjunction with rhu interleukin 3 (rhuIL-3), rhu interleukin 6 (rhuIL-6), and/or rhu granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) under the same culture conditions. The cloning enhancing effect elicited by human IL-9 is Epo dependent, although IL-9 alone sustains the survival of erythroid progenitor cells in vitro, as assessed by delayed additions of Epo to the cultures. The ability of human IL-9 to stimulate BFU-E and CFU-E colony formation using low numbers of highly enriched progenitor cells in serum-depleted conditions demonstrates the direct effect of IL-9 on erythroid progenitors and implicates its potential role in the enhancement of erythropoiesis.

Antigens, CD↗
PubMed1992

Interleukin-4 may contribute to the abundant T-cell reaction and paucity of neoplastic B cells in T-cell-rich B-cell lymphomas.

T-cell-rich B-cell lymphomas (TCRBCLs) are diffuse lymphomas that contain a minority of large neoplastic B cells amidst a majority of non-neoplastic T cells and numerous histiocytes, an unusually pronounced reactive component not seen in most diffuse large B-cell lymphomas (DLBCLs). This reaction may be influenced by various cytokines secreted by lymphoma or reactive cells; therefore, expression of interleukin (IL)-1 beta, IL-2, IL-4, IL-6, and IL-9 was evaluated immunohistochemically on paraffin-embedded sections of 18 TCRBCLs and was compared with that of 15 DLBCLs containing a minority of reactive T cells and to that of seven reactive lymph nodes. Moderate to intense expression of IL-4 was detected in variable numbers of tumor cells and in numerous histiocytes in 16 TCRBCLs. In contrast, intense IL-4 expression in numerous histiocytes was observed in only one of 15 DLBCLs with few T cells. In four other DLBCLs and three reactive nodes, moderate to intense staining for IL-4 was noted only in rare large transformed cells or in occasional histiocytes. Except for one IL-1 beta positive and another IL-9 positive TCRBCL, there was no marking or weak staining only with other cytokine antibodies in the neoplastic and reactive cases studied. The expression of IL-4 in most TCRBCLs, but not in other DLBCLs or in reactive nodes, suggests that this cytokine is one factor involved in the pathobiology of the abundant T-cell reaction and, perhaps, contributes to the paucity of neoplastic B cells in TCRBCLs.

B-Lymphocytes↗
PubMed1992

IL-2 dependence of IL-9 expression in human T lymphocytes.

Human IL-9 is a T cell-derived lymphokine that is abundantly expressed upon activation with mitogens. The observation that IL-9 induction peaks as late as 28 h after stimulation suggested the involvement of secondary signals in this process. The finding reported here that IL-9 expression is blocked by cycloheximide strongly supports this hypothesis. Moreover, we identify IL-2 as the critical element controlling IL-9 expression in T cells. We show (i) that anti-IL-2R antibodies block IL-9 expression in T cells stimulated with PMA and anti-CD3 and (ii) that IL-2, of a panel of cytokines, is the only molecule that synergizes with PMA for IL-9 induction. The latter finding is confirmed in a T cell leukemia line. Finally, we demonstrate that IL-2 plays a regulatory role in the induction of other cytokines, such as IL-4, IL-5, IL-6, and granulocyte/macrophage-CSF, in fresh peripheral T cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Recombinant murine interleukin 9 enhances the erythropoietin-dependent colony formation of human BFU-E.

Murine interleukin 9 (mIL-9) is a novel T-cell-derived lymphokine previously described as a T-cell growth factor (P40/TCGFIII) and as a mast cell growth-enhancing activity (MEA). In the present study we examined the potency of recombinant (r)mIL-9 to exhibit hemopoietic growth factor activity in the human system. In semisolid cultures of normal human bone marrow-derived mononuclear cells, rmIL-9 alone at a concentration range from 25 to 200 U/ml did not reveal any colony-stimulating activity on human granulocyte-macrophage colony-forming cells (GM-CFC), erythroid colony-forming units (CFU-E), and erythroid burst-forming units (BFU-E). Furthermore, we did not observe synergistic effects of rmIL-9 on the number, size, and morphological composition of human granulocyte-macrophage colonies in cultures stimulated with giant cell tumor-conditioned medium. However, a synergistic effect of rmIL-9 in the human erythropoietic culture system was clearly demonstrated in the presence of recombinant human erythropoietin (rhEpo). Recombinant murine IL-9 at a concentration of 200 U/ml enhanced the number of BFU-E-derived day-14 colonies about 3.6-fold as compared to control cultures stimulated with Epo alone. The formation of CFU-E-derived day-7 colonies was not significantly altered under the same conditions. Our results demonstrate that in the presence of rhEpo, rmIL-9 is synergistically active in human bone marrow cultures as an erythroid burst-promoting factor. The development of granulocyte-macrophage colonies obviously is not affected. This finding strongly suggests that mIL-9 can mediate signals via human IL-9 receptors and further extends the range of biological activities hitherto ascribed to mIL-9.

Animals↗
PubMed1992

Murine interleukin 9 stimulates the proliferation of mouse erythroid progenitor cells and favors the erythroid differentiation of multipotent FDCP-mix cells.

Murine interleukin 9 (mIL-9) is a T-cell-derived growth factor that stimulates erythroid burst-forming units (BFU-E) from murine bone marrow. We further investigated this activity using enriched mouse bone marrow progenitors and the multipotent interleukin 3 (IL-3)-dependent FDCP-Mix cell line. We report here that mIL-9 stimulates erythroid burst formation of total bone marrow cells and accessory cell-depleted bone marrow cells, even in serum-free cultures. On the other hand, we observed that although mIL-9 could not support proliferation of FDCP-Mix cells, it favors erythroid differentiation of these cells in the presence of both IL-3 and erythropoietin. These results strongly suggest that mIL-9 acts directly on mouse erythroid progenitor cells.

Animals↗
PubMed1991

IL-1 serves as a secondary signal for IL-9 expression.

IL-9 is produced in vitro by activated CD4+ T cell lines of the Th2 subtype and by naive CD4+ T cells. Here we show that T cell lines stimulated with Con A in the presence of accessory cells (AC) such as irradiated spleen cells or bone marrow-derived macrophages produced substantially more IL-9 than T cells stimulated with Con A alone. These data suggest that AC influence the production of IL-9 through accessory signals that result in an at least 10-fold increase of IL-9 secretion by the respective T cells. Addition of IL-1 to T cells activated by Con A, PHA, or anti-CD3 antibodies revealed that this monokine was responsible for the potentiation of IL-9 production. This finding was confirmed by applying anti-IL-1 antibodies. The production of other lymphokines, namely, IL-3, IL-4, and IL-6, by activated T cells was not or only marginally enhanced in the presence of AC or IL-1, thus indicating that the synthesis of IL-9 is regulated differently from that of other Th2-derived lymphokines. Furthermore, it was demonstrated by Northern blot analysis that IL-1 increases IL-9 expression at the pretranslational level. Because IL-1 alone failed to induce the production of IL-9 by T cells, this monokine acts as a costimulator in combination with a T cell receptor-mediated signal.

Animals↗
PubMed1991

Early fetal hematopoietic development from in vitro differentiated embryonic stem cells.

In this report we describe the efficient hematopoietic differentiation of embryonic stem (ES) cells in vitro. When cultured in semisolid medium two of five ES cell lines efficiently generated embryoid bodies (EBs) containing blood islands in which hematopoietic cells from all six myeloid lineages could be detected. Among a variety of growth factors tested, only erythropoietin significantly increased blood island formation. We directly demonstrate the presence of hematopoietic progenitors in the EBs by employing an in vitro precursor assay. Colony-forming cells (CFC) of all myeloid lineages as well as bi- and multipotent (CFC-MIX) progenitors were readily identified, and a detailed time-course analysis of their appearance was performed. Despite a high frequency of CFC-MIX in vitro, we did not observe any spleen colony-forming cells (CFU-S) in vivo. We conclude that hematopoietic differentiation of ES cells under these conditions reflects formation of the complete range of blood cells found in the yolk sac of the early fetus. Therefore this system provides a unique model in which to study the earliest events of hematopoietic development in vitro.

Animals↗
PubMed1992

Interleukin 9 is expressed by primary and cultured Hodgkin and Reed-Sternberg cells.

We show by mRNA hybridization analysis and immunostaining using a mouse monoclonal antibody (moAb) to recombinant human interleukin 9 (IL-9) that both primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells produce IL-9 transcripts and protein and express surface binding sites for IL-9. In addition, the growth of H-RS cells obtained from the HDLM-2 line (abundantly producing IL-9 transcripts) was significantly inhibited when anti-IL-9 moAb or an IL-9 antisense oligodeoxyribonucleotide was added to cultures. Excess addition of recombinant human IL-9 relieved the effects of anti-IL-9 moAb on HDLM-2 growth. Growth of H-RS cells of the KM-H2 line, which displays only low amounts of IL-9 detectable upon hybridization of polyadenylic acid-selected RNA only, was not affected by anti-IL-9 moAb. The proliferative capacity of KM-H2 cells in soft agar and liquid suspension cultures was, however, augmented at least 3-fold when cells were exposed to recombinant human IL-9. In conclusion, our results show that IL-9 is expressed by H-RS cells and point to a possible role of this molecule as a growth factor for these cells.

Antibodies, Monoclonal↗
PubMed1990

Tumor necrosis factor-alpha and P40 induce day 15 murine fetal thymocyte proliferation in combination with IL-2.

Cytokines are known to play a key role in the development of several hemopoietic lineages including lymphocytes. Two cytokines: IL-4 (in the presence of PMA) and IL-7 have been shown to induce immature fetal thymocyte proliferation. It has also been suggested that IL-2 plays an important role in fetal T cell development. In this report, we investigated the effects of several cytokines (known to be growth factors for T-lineage cells) on fetal thymocyte proliferation. Our results indicate that: 1) TNF-alpha and a newly described cytokine, P40, enhance fetal thymocyte proliferation stimulated by IL-2 (but not IL-4 or IL-7). 2) The enhancement induced by P40 is not mediated by TNF-alpha because blocking antibodies against this cytokine failed to inhibit this response. 3) IL-4 inhibits fetal thymocyte proliferation in response to TNF-alpha + IL-2 or to IL-7 but not to P40 + IL-2. Finally, 4) the proliferating cells to all cytokine combinations used were Thy-1+. These observations suggest that these cytokine combinations induce independent pathways of T cell proliferation in the developing thymus.

Animals↗
PubMed1990

Human P40/IL-9. Expression in activated CD4+ T cells, genomic organization, and comparison with the mouse gene.

P40 is a cytokine that was originally identified in the mouse as a T cell growth factor, but whose spectrum of potential targets was recently shown to include mast cells as well as megakaryoblastic leukemic cells. Given these multiple activities, it was proposed that the protein be renamed IL-9. The analysis of P40 genomic clones reported here shows that the human and mouse P40 genes consist of 5 exons spread over approximately 4 kb of DNA and organized in a similar fashion in both species. The two genes exhibit a high degree of identity in the coding sequence and in the 5' untranslated regions, which contain, among other consensus motifs, a conserved sequence for the binding of AP-1. Expression of human P40 was studied in PBMC. Treatment of the cells with PMA and a calcium ionophore induced strong expression of a 0.7-kb P40 mRNA. No message was detected in unstimulated cells or in cells stimulated with LPS or Staphylococcus aureus, indicating that P40 expression is not constitutive and suggesting that the gene is not easily activated in B lymphocytes and in monocytes. By contrast, T cell mitogens such as PHA or anti-CD3 antibodies induced a substantial P40 expression that was further enhanced in the presence of PMA. Cell fractionation experiments indicated that, under these conditions, the protein is preferentially induced in CD4+ T cells. The induction of P40 by anti-CD3 antibodies suggests that P40 production is part of the normal T cell response to antigenic stimulation.

Amino Acid Sequence↗