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At least 19 recordsLinked to original sources
PubMed1992

Human interleukin-9 supports formation of a subpopulation of erythroid bursts that are responsive to interleukin-3.

We have investigated the biological activities of recombinant human interleukin-9 (IL-9) on enriched hematopoietic progenitors, alone or in combination with other cytokines, including Epo, G-CSF, IL-3, and GM-CSF, under serum-containing and serum-free cultures. IL-9 alone did not support colony formation. However, IL-9 plus Epo induced erythroid burst (BFU-E) formation derived from peripheral blood (PB) progenitors. Delayed addition experiments demonstrated that a part of bone marrow (BM) derived BFU-E, which seems to be immature, only responded to IL-9 and formed erythroid bursts. The burst-promoting activity (BPA) of IL-9 was confirmed using neutralizing aIL-3, aGM-CSF, and aIL-9 antisera and serum-free culture. IL-9 supported a part of BFU-E population that respond to IL-3, which was almost identical to the number of BFU-E supported by GM-CSF. IL-9 had no additive effect on erythroid and mixed colony formation supported by IL-3. In contrast, IL-9 showed an additive effect on erythroid burst formation supported by GM-CSF in serum-free culture. These data suggest that IL-9 and GM-CSF act on distinct IL-3-responsive BFU-E population. In addition, delayed addition experiment clearly demonstrated that IL-9 supports survival and the early stage of proliferation of BFU-E. These results led us to propose that IL-9 possibly acts as a BPA and selectively supports a subpopulation of early class of BFU-E that respond to IL-3.

Cell Division↗
PubMed1991

Regional localization of the human glutaminase (GLS) and interleukin-9 (IL9) genes by in situ hybridization.

Phosphate-activated glutaminase is found in mammalian small intestine, brain, and kidney, but not in liver. The enzyme initiates the catabolism of glutamine as the principal respiratory fuel in the small intestine, may synthesize the neurotransmitter glutamate in the brain, and functions in the kidney to help maintain systemic pH homeostasis. Interleukin-9 (IL9) is a relatively new cytokine that supports the growth of helper T-cell clones, mast cells, and megakaryoblastic leukemia cells. cDNA clones have recently been obtained for each of these genes. The human loci for phosphate-activated glutaminase (GLS) and IL9 have previously been mapped to chromosomes 2 and 5, respectively, by analysis of somatic cell hybrid DNAs. By using chromosomal in situ hybridization, we have regionally mapped GLS to 2q32----q34 and IL9 to 5q31----q35.

Animals↗
PubMed1992

Recombinant human interleukin-9 induces protein tyrosine phosphorylation and synergizes with steel factor to stimulate proliferation of the human factor-dependent cell line, M07e.

Human interleukin-9 (IL-9) was originally identified and cloned based on its stimulatory effect on proliferation of human myeloid cell line, M07e. IL-9 synergized with Steel factor, the ligand for the c-kit product, to stimulate M07e cell proliferation. To investigate potential mechanisms for this, IL-9 was assessed for effects on protein tyrosine kinase activities in M07e cells by immunoblotting with anti-phosphotyrosine monoclonal antibody; results were compared with those of Steel factor alone and in combination with IL-9, and those of 12-0-tetradecanoyl phorbol-13-acetate (TPA). Recombinant human IL-9 (10 ng/mL) rapidly and transiently induced or enhanced at least four tyrosine phosphorylated protein bands with molecular weights of 105, 97, 85, and 81 Kd. This tyrosine phosphorylation pattern was different from that generated by recombinant murine Steel factor or TPA stimulation and the combination of IL-9 and Steel factor did not change the IL-9-induced pattern. IL-9-induced tyrosine phosphorylated bands were completely blocked by treatment of IL-9 with anti-IL-9 antibody under conditions that also neutralized the synergistic effect of IL-9 with Steel factor on M07e cell proliferation. Genistein, a tyrosine kinase inhibitor, blocked phosphorylation of IL-9 and Steel factor-induced bands. Unlike Steel factor or TPA, IL-9 did not appear to stimulate phosphorylation of 42-Kd mitogen-activated protein (MAP) kinase or Raf-1, or enhance MAP kinase activity. MAP kinase and Raf-1 are serine/threonine kinases that are phosphorylated and activated by many growth factors and by agonists for protein kinase C. While the combination of IL-9 plus SLF did not appear to induce phosphorylation of new bands not already seen with either IL-9 or SLF alone, or enhance the phosphorylation of those bands seen with either cytokine alone, the results suggest that IL-9 activates specific and unique signal transduction pathways.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1990

Human P40 T-cell growth factor (interleukin-9) supports erythroid colony formation.

Because human P40 T-cell growth factor, tentatively designated interleukin-9 (IL-9), was isolated through its ability to stimulate a human IL-3-dependent leukemic cell line (M-O7E), we tested the ability of IL-9 to support the growth and differentiation of normal hematopoietic progenitor cells from peripheral blood and bone marrow. Although the M-O7E cell line was derived from a patient with megakaryoblastic leukemia, IL-9 has not proved to be a growth or maturation factor for megakaryocytes, but instead has proved to be effective in supporting the development of erythroid bursts (BFU-E) in cultures supplemented with erythropoietin. Using highly purified progenitors from peripheral blood, IL-3 showed a BFU-E plating efficiency of 46% compared with 20% for IL-9. Because of the purity of these cell preparations and the low cell density in culture, IL-9 is likely to interact directly with erythroid progenitors. Analysis of mixing experiments and of the morphology of the BFU-E in culture indicated that IL-9 interacts preferentially with a relatively early population of IL-3-responsive BFU-E. In cultures of human bone marrow or cord blood, IL-9 selectively supported erythroid colony formation, while IL-3 and granulocyte/macrophage colony-stimulating factor additionally yielded granulocyte/macrophage colonies. Therefore, IL-9 represents a new T cell-derived cytokine with the potential for selectively stimulating erythroid development in the hematopoietic system.

Antigens, CD↗
PubMed1992

Human interleukin-9: a new cytokine in hematopoiesis.

IL-9 was first identified in the mouse system as a T cell growth factor while human IL-9 was isolated based on its activity on a human myeloid leukemic cell line. The high sequence homology between mouse and human IL-9 plus the preliminary biological analysis have predicted a wide spectrum of in vitro biological activities for this cytokine. Despite the high sequence homology between mouse and human IL-9, many biological activities, however, have not been demonstrated in both species. In vivo studies therefore become essential to understand the physiological role of IL-9. Increasing evidence have also suggested the possible role of IL-9 in the pathogenesis of HD and LCAL. Detailed analysis of IL-9 expression, autocrine growth and clinical outcome of HD patients will be required to make any speculation on the role of this cytokine in the disease states.

Animals↗
PubMed1992

[Function, molecular structure and gene expression regulation of interleukin 9 (IL-9)].

Interleukin-9 (IL-9)/P40 is a recently reported murine growth factor for helper T-cell clones. It is produced by ConA stimulated CD4+ T-cells or several T-cell lines such as TUC 2.15 derived from C57Bl/6 mouse. In the murine system, IL-9/P40 directly supported proliferation of mucosal type mast cells, and also induced erythroid burst formation, indirectly. On the other hand, human IL-9, which is a homologue to murine P40, was cloned from a cDNA library prepared with mRNA isolated from PHA-induced T-cell line (C5MJ2). Analysis of the sequence of cDNA revealed a striking similarity between murine and human IL-9/P40. Human IL-9 supported formation of a subpopulation of erythroid bursts that are responsive to IL-3. In this communication, identification, cloning of cDNA, and biological activities of murine and human IL-9/P40 are discussed.

Animals↗
PubMed1992

Expression cloning of the murine and human interleukin 9 receptor cDNAs.

Interleukin 9 (IL-9) is a T-cell-derived lymphokine that induces the proliferation of various lymphoid and hemopoietic cells. A cDNA clone encoding the murine IL-9 receptor was isolated by expression cloning in COS cells and screening with 125I-labeled IL-9. Transient expression of this cDNA produced high-affinity binding sites for IL-9. The predicted 52-kDa protein contains a putative signal peptide and a typical transmembrane domain. A cDNA for the human homologue was isolated by cross-hybridization. Transfection of this cDNA in a murine T-cell clone conferred responsiveness to human IL-9. Sequence analysis revealed that the IL-9 receptor belongs to the recently described hematopoietin receptor super-family and is expressed in membrane-bound and soluble forms.

Amino Acid Sequence↗
PubMed1992

Human growth factor for murine interleukin (IL)-9 responsive T cell lines: co-induction with IL-6 in fibroblasts and identification as LIF/HILDA.

Two mouse helper T cell clones that proliferate in response to murine interleukin (IL)-9 could also be grown in conditioned medium of stimulated human connective tissue cells. The activity was not due to known T cell growth factors including human IL-9, which is not effective on mouse cells. This growth-stimulatory activity for TS1 cells (GATS) was co-induced with IL-6 on normal fibroblasts and certain sarcoma cell lines stimulated with IL-1, double-stranded RNA, virus or phorbol ester. However, the conditions for optimal induction and the kinetics of production were found to be different for IL-6 and GATS. GATS from phorbol ester-stimulated human hepatosarcoma cells co-purified with IL-6, but could be separated from it by subsequent cation-exchange fast-protein liquid chromatography and reverse-phase high-performance liquid chromatography. Homogeneous tumor cell-derived GATS was a 25-kDa protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, whereas IL-6 produced by these cells appeared in its 23-kDa form. Pure GATS was found to be inactive in the B cell hybridoma growth assay for IL-6. Finally, GATS was identified by NH2-terminal sequence analysis of the mature protein as leukemia inhibitory factor or human interleukin for DA cells (LIF/HILDA). The effect of LIF/HILDA on T cells was not mediated by IL-2, IL-4 or IL-9 production. Since this cytokine has not previously been reported to act on T cells, further investigation of its role in T cell activation should be taken into consideration.

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↗
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↗