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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-3 (IL-3) regulates growth and differentiation of multipotential as well as lineage-committed progenitor cells. The human IL-3 receptor (IL-3R) consists of the alpha and common beta (beta c) subunits. The alpha subunit (IL-3R alpha) is specific for IL-3 and binds IL-3 with low affinity. In contrast, the beta c subunit does not bind any cytokine by itself, but forms a high-affinity receptor with IL-3R alpha. As the same beta c subunit also forms high-affinity receptors for IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) with the respective cytokine-specific alpha subunit, the expression of the alpha subunits is responsible for specificity of cytokines. To examine the expression of IL-3R alpha, we have developed a monoclonal antibody (MoAb), N3A. N3A specifically bound to cells expressing IL-3R alpha and immunoprecipitated a 75 Kd glycoprotein, which became 43 Kd on N-glycosidase digestion. N3A and an anti-beta c antibody, CRS1, were used in double color fluorescence-activated cell sorter (FACS) staining with several lineage markers to see the IL-3R expression pattern in peripheral blood (PB), cord blood (CB), and bone marrow (BM) cells. Both IL-3R subunits were expressed on myeloid cell lineages (CD13+, CD14+, CD15Lo, or CD33+). To further study the IL-3R expression on hematopoietic progenitor cells, the CD34+ populations were isolated from both BM and CB cells. Those populations showed positive staining profiles with the N3A MoAb and were weakly stained with the CRS1 MoAb. Furthermore, anti c-kit antibody staining of the CD34+ fraction from CB, but not from BM, showed two intensities and the IL-3R alpha expression seemed to be higher in a fraction of low c-kit expression. Because IL-1, IL-6, G-CSF, stem cell factor (SCF), interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha are known to enhance IL-3-dependent colony formation, we have examined whether this enhancement could be correlated with upregulation of the IL-3R expression. Incubation of CD34+ cells with TNF-alpha for 2 days significantly increased the level of beta c and G-CSF increased the number of cells with high level expression of alpha, while other factors did not affect the IL-3R expression. Thus, different cytokines appear to have different mechanisms for enhancement of IL-3-dependent proliferation.
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PMID:Expression and factor-dependent modulation of the interleukin-3 receptor subunits on human hematopoietic cells. 768 90

The effects of recombinant human stem cell factor (SCF, a c-kit ligand) on an eosinophil lineage were examined in clonal and suspension cultures of human non-adherent light density bone marrow cells. Although interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-5 (IL-5) each exhibited eosinophil-colony stimulating activity, SCF did not do so alone. However, the addition of SCF to IL-3, GM-CSF, or IL-5 cultures led to an increase in the number of eosinophil colonies per 5 x 10(4) cells, from 8.0 +/- 1.4, 11.0 +/- 2.0, and 6.7 +/- 0.6, to 12.7 +/- 3.2, 19.0 +/- 4.4, and 12.0 +/- 2.0, respectively. A similar synergistic effect of SCF on eosinophils was also observed in the suspension cultures of bone marrow cells, although SCF alone had little proliferative effect. Moreover, although the delayed addition of IL-5 to cultures containing SCF led to a small increase in the number of mature eosinophils, the effect of SCF was less than that of either GM-CSF or IL-3. These observations suggest that SCF may have a proliferative effect on eosinophil precursor cells and may increase the number of mature eosinophils when used in combination with such other growth factors as IL-3, GM-CSF, and IL-5.
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PMID:Effect of c-kit ligand (stem cell factor) in combination with interleukin-5, granulocyte-macrophage colony-stimulating factor, and interleukin-3, on eosinophil lineage. 769 27

Basophils and mast cells represent important effector cells in allergic inflammation. Furthermore, these cell types are suggested to play a role in the pathogenesis of other forms of chronic inflammation and in the maintenance of tissue homeostasis. Recent studies provided new information on the morphology, development, distribution and effector function of the histamine-containing cells. Particularly the identification of new surface membrane molecules such as CD40 ligand on basophils or c-kit on mast cells, and of new triggering agents and modulators of mediator release such as IL-3, IL-5, GM-CSF and nerve growth factor (for basophils) or c-kit ligand (for mast cells) allows a better understanding of the regulation of these cell types. The regulating cytokines are produced by lymphocytes and tissue cells. On the same time, membrane proteins and soluble mediators of basophils and mast cells regulate tissue and immune functions. Thus, basophils and mast cells are not only effectors but also regulators of inflammation. It is, therefore, tempting to speculate that both cell types play an important role as mediator cells between the unspecific effector level and the specific antigen-recognizing cells of the host immune defense system. This review is mostly restricted to the human system.
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PMID:[Human basophilic granulocytes and mast cells: mediators between allergic inflammation and the specific immune system]. 792 73

An ultrastructural morphological primer of human eosinophils is presented. Mature and immature eosinophils, obtained from peripheral blood and bone marrow, as well as activated tissue eosinophils are all used to illustrate the various morphologies assumed by eosinophils in vivo. The various ultrastructural changes expressed by this cell lineage in vivo reflect the impact of differentiation, maturation, activation, secretion, and cell injury on morphology. Nearly all of the changes described in vivo are also evident in eosinophils arising in in vitro systems. We review published studies of these culture systems, which have been supplemented with various conditioned media containing naturally occurring growth factor(s) that are permissive (or not permissive) for eosinophils or with the recombinant growth factors, IL-5 or IL-3. These studies were helpful in the recognition of eosinophil-promoting, -sustaining and -activating properties of human IL-3 and IL-5. Moreover, mature and immature eosinophils were shown to release a granule matrix protein--eosinophil peroxidase (EPO)--by its transport in small cytoplasmic vesicles, a process termed piecemeal degranulation (PMD), accounting for the gradual emptying of granule contents in the absence of granule fusions to the plasma membrane. Also presented are eosinophil morphologies that occur in vitro in suspension cultures of human cord blood supplemented with the c-kit ligand from various sources. The wide variety of eosinophil subcellular changes in the c-kit ligand-supplemented cultures, like the changes of which eosinophils are capable in vivo, reflects the processes of differentiation, maturation, activation, secretion and cell injury. Presentation of this ultrastructural morphological primer of human eosinophils in vitro should enable investigators to recognize eosinophils in all of their diverse morphologic forms in cultures that contain differentiating and functioning members of other lineages, also present in c-kit ligand-supplemented cultures. These lineages include mast cells, basophils, neutrophils, monocytes, macrophages, megakaryocytes, and endothelial cells.
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PMID:Human eosinophils in vitro. An ultrastructural morphology primer. 807 95

Mast cells and basophils are multifunctional effector cells of the immune system. Both are myeloid cells and originate from multipotent hemopoietic progenitor cells. Usually, human basophils complete their differentiation in the bone marrow. In contrast, mast cells usually undergo differentiation in extramedullary organs. During the past few years, growth factors for human basophils and a growth factor for human mast cells have been identified. Interleukin-3 is the most potent differentiation factor for human basophils and activates mature basophils via high affinity binding sites. Other basophil agonists are GM-CSF, IL-5, NGF and certain chemokines (IL-8, MCP-1). Mast cells apparently loose cytokine binding sites during mastopoiesis and as mature cells, do not express detectable amounts of IL-3R, GM-CSFR or IL-8R. However, in contrast to other myeloid cells, mast cells express SCF receptor/c-kit during mastopoiesis and on mature cells. Furthermore, the ligand of c-kit, SCF, induces differentiation of human mast cells from their progenitor cells and upregulates effector functions in mature mast cells.
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PMID:Cytokines involved in growth and differentiation of human basophils and mast cells. 852 98

Cytokines transduce their signals through specific receptors. Receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5 share the common signal transducing subunit (beta c), whereas the alpha subunits function as specific ligand binding components. In this study we prepared specific mouse monoclonal antibodies against human GM-CSF receptor-alpha subunit (hGMR alpha) by immunizing mice with Ba/F3 cells transfected with hGMR alpha complementary DNA. Using these anti-hGMR alpha antibodies in combination with antibodies against IL-3 receptor-alpha (IL-3R alpha), beta c subunits, and c-kit, we examined expression patterns and modulation of these receptor subunits on several human hematopoietic cells, including CD34+ cells and leukemic cell lines. GMR alpha and IL-3R alpha were expressed on GM-CSF- and IL-3-responsive cell lines, such as TF-1 and UT-7, whereas the expression levels were much lower on UT-7E, a GM-CSF- and IL-3-unresponsive subline of UT-7. The GMR alpha subunit was expressed only on mature granulocytes and monocytes, and IL-3R alpha was expressed on monocytes but not on mature granulocytes, and none of these subunits were expressed on lymphocytes. For CD34+ cells, GMR alpha was expressed more abundantly on CD34+ CD33high cells than on CD34+ CD33low cells, whereas IL-3R alpha was expressed more abundantly on CD34+ CD33low cells than on CD34+ CD33high and CD34+ CD33neg cells. Slight but significant expression of the beta c subunit was detected on CD34+ cells. Expression of not only GMR alpha and IL-3R alpha subunits but also c-kit was specifically downregulated by 48-hour incubation with their respective ligands. Receptor transmodulation between GM-CSF, IL-3, and stem cell factor (or kit ligand) was not detected on CD34+ cells in 48-hour cultures. We also detected upregulation of these alpha subunits by IL-1 alpha and interferon-gamma on leukemic cell lines. Our study showed expression levels for each receptor subunit--including GMR, IL-3R, and c-kit on human bone marrow and peripheral blood cells and leukemic cell lines--and revealed differential regulation of the expression of the receptor subunits.
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PMID:Differential expression of granulocyte-macrophage colony-stimulating factor and IL-3 receptor subunits on human CD34+ cells and leukemic cell lines. 854 66

B cells originate from pluripotent hematopoietic stem cells and differentiate in the bone marrow into mature B cells. The differentiation of a stem cell into a mature B cell can be subdivided into five steps: early pro-B cells, late pro-B cell stage, pre-B cell stage, immature B cells, and mature B cells. Each differentiation step appears to be regulated by co-receptor and cytokines. The earliest B-cell progenitors are bound to the stromal cell surface by adhesive interactions through cell surface molecules to promote the binding of c-kit to stem cell factor (SCF). At the late pro-B cell stage, interleukin-7 (IL-7) induces proliferation and differentiation of pro-B cells to pre-B cells. Surface Ig-expressing mature B cells leave bone marrow and circulate into peripheral lymphoid organs in which they can be activated to proliferate and to differentiate into antibody-secreting cells by encountering antigens and "helper" T (TH) cells. TH cells activate B cells by their products, cytokines such as IL-4, IL-5, and IL-6, and membrane-bound stimulatory molecules including CD40 ligand. Each cytokine has pleiotropic activity on B cells and other cell types, and acts through a specific receptor. Abnormal expression of a cytokine receptor and aberrant signal transduction causes functional abnormality of B cells.
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PMID:Cytokines involved in B-cell differentiation and their sites of action. 916 40

Murine studies have demonstrated that, as with other nematodes, infection with the intestinal nematode Trichinella spiralis is associated with a pronounced intestinal mastocytosis, eosinophilia and an elevation in serum levels of total IgE. Both interleukin (IL)-4 and IL-5 are clearly important in the generation of IgE responses and eosinophilia, respectively, but the control of mucosal mastocytosis in vivo is not as well defined. Mucosal mast cells appear to be particularly important with regard to T. spiralis infections as there is good evidence to suggest their involvement in expulsion of the parasite from the host. In this study we examined the effect of the overproduction of the Th2 cytokine IL-9 on infection with this nematode. We demonstrate that naive IL-9-transgenic mice have an intense intestinal mastocytosis and high serum levels of mouse mast cell protease-1. Moreover, upon infection high titers of parasite-specific IgG1 were observed with a heightened mast cell response, which was associated with the rapid expulsion of T. spiralis from the gut. Furthermore, as depression of this mast cell response, using anti-c-kit antibodies, resulted in the inability of these mice to expel the parasite, this study clearly demonstrates an activity of IL-9 on mucosal mastocytosis and the host protective immune response in vivo.
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PMID:Interleukin-9 is involved in host protective immunity to intestinal nematode infection. 936 7

The receptors for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 share a common signaling subunit betac. However, in the mouse, there is an additional IL-3 signaling protein, betaIL-3, which is specific for IL-3. We have previously reported that IL-3 abrogates the lymphoid potentials of murine lymphohematopoietic progenitors and the reconstituting ability of hematopoietic stem cells. We used bone marrow cells from betac- and betaIL-3-knock-out mice to examine the relative contributions of the receptor proteins to the negative regulation by IL-3. First, we tested the effects of IL-3 on lymphohematopoietic progenitors by using lineage-negative (Lin-) marrow cells of 5-fluorouracil (5-FU)-treated mice in the two-step methylcellulose culture we reported previously. Addition of IL-3 to the combination of steel factor (SF, c-kit ligand) and IL-11 abrogated the B-lymphoid potential of the marrow cells of both types of knock-out mice as well as wild-type mice. Next, we investigated the effects of IL-3 on in vitro expansion of the hematopoietic stem cells. We cultured Lin-Sca-1-positive, c-kit-positive marrow cells from 5-FU-treated mice in suspension in the presence of SF and IL-11 with or without IL-3 for 7 days and tested the reconstituting ability of the cultured cells by transplanting the cells into lethally irradiated Ly-5 congenic mice together with "compromised" marrow cells. Presence of IL-3 in culture abrogated the reconstituting ability of the cells from both types of knock-out mice and the wild-type mice. In contrast, addition of GM-CSF to the suspension culture abrogated neither B-cell potential nor reconstituting abilities of the cultured cells of wild-type mice. These observations may have implications in the choice of cytokines for use in in vitro expansion of human hematopoietic stem cells and progenitors.
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PMID:Negative regulation by interleukin-3 (IL-3) of mouse early B-cell progenitors and stem cells in culture: transduction of the negative signals by betac and betaIL-3 proteins of IL-3 receptor and absence of negative regulation by granulocyte-macrophage colony-stimulating factor. 968 Mar 58

Histogenetically, the thymus is the primary lymphopoietic organ and provides an optimal microenvironment for the differentiation of T lymphocytes, independently of the influence of foreign antigens. Lymphocytes with diverse potential are produced in a protective microenvironment optimal for their maturation, whose dual cellular network is provided by endodermally derived RE cells and numerous ectomesenchymal cells derived from the neural crest. The full development of intrathymic hematopoiesis depends upon the successful completion of a series of well coordinated cellular interactions between widely divergent (in terms of origin) cells [epithelium (primitive pharynx); ectomesenchyrne (neural crest); and PHSCs (yolk sac, fetal liver)]. The cells of the thymic epithelial primordium do not proliferate in the absence of "inductive" interactions with the ectomesenchyme. Moreover, the nature of the mesenchyme determines the behavior of the thymic epithelial anlagen. The ectomesenchymal origin of chemotactic stem cell factor secretion, responsible for hemopoietic stem cell immigration, is a distinct possibility. The human thymus is a generalized hematopoietic tissue with between 7 to 9 weeks of ontogenesis. In human and dog fetuses various elements of mammalian hematopoiesis were identified intrathymically: B lymphocytes, plasma cells, erythropoietic and granulocytopoietic (neutrophils and eosinophils) cells, antigen presenting dendritic cells, and mast cells. Our light and ultrastructural (transmission and scanning), as well as immunocytochemical observations have established that during the embryonal and fetal period, the thymus is seeded by pluripotent, yolk sac derived PHSCs characterized by the following immunophenotype CD34+CD43+CD38-Lin-HLA-DR+CD69+. Stem cell c-kit tyrosine kinase (also referred to as mast cell growth factor, stem cell factor, or steel factor) in combination with autocrine and paracrine growth factors and cytokines (IL-3, IL-4, IL-5, IL-6, IL-7, G-CSF, etc.) stimulates myelopoiesis, including erythropoiesis, as well as lymphopoiesis. These hematopoietic growth factors are produced by activated lymphoblastic cells and stromal RE cells under the influence of immunoneuroendocrine regulation, supported by the finding that experimental or spontaneous, in vivo neural crest ablation during early mammalian ontogenesis always results in an abnormal development of the thymus, as well as the heart and great vessels, thyroid, and parathyroid glands.
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PMID:Intrathymic non-lymphatic hematopoiesis during mammalian ontogenesis. 989 Dec 23


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