Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The view that the two isoforms of prostaglandin-endoperoxide synthase (cyclooxygenase), PGHS-1 and PGHS-2, mediate physiologic and inflammatory processes, respectively, implies separate pathways of arachidonic acid metabolism with different benefits to the host. Functional segregation of these steps in endogenous arachidonic acid metabolism in a single cell in response to different stimuli is now demonstrated. When mouse bone marrow-derived mast cells developed in interleukin-3 (IL-3)-containing medium were cultured with c-kit ligand in combination with IL-10 and IL-1 beta, transient expression of PGHS-2 mRNA and protein occurred in a dose- and time-dependent fashion, accompanied by substantial release of prostaglandin D2 (PGD2) into the culture medium from 2 to 10 h. In contrast, induction of PGHS-2 did not mediate an increase in PGD2 generation in response to stimulation with IgE and antigen. After a longer period of culture, from 24 to 48 h, the expression of PGHS-1 increased, as did the increase in IgE/antigen-dependent generation of PGD2. Dexamethasone, which inhibited the induction of PGHS-2 but not PGHS-1, and a PGHS-2-selective inhibitor suppressed cytokine-induced PGD2 generation but not IgE-dependent PGD2 generation. Thus, at a time when both PGHS-1 and PGHS-2 are present in bone marrow-derived mast cells, they function independently by coupling to different stimulus-initiated pathways to PGD2 generation from endogenously derived arachidonic acid.
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PMID:Prostaglandin endoperoxide synthase-1 and -2 couple to different transmembrane stimuli to generate prostaglandin D2 in mouse bone marrow-derived mast cells. 807 53

Mast cells and basophils are offspring of the multipotential hematopoietic stem cell. Although mast cells sometimes are misunderstood as basophils that have invaded connective or mucosal tissue, these two kinds of basophilic cells are distinguishable by morphology and surface antigenicity. Developmental processes of mast cells and basophils are different. Basophils complete their differentiation within the bone marrow, but precursors of mast cells leave the bone marrow, invade connective or mucosal tissue, proliferate, and differentiate into mast cells. The mechanisms regulating development are different between mast cells and basophils. Both T cell-dependent and fibroblast-dependent mechanisms are involved in the development of rodent mast cells, but only the fibroblast-dependent mechanism is known for development of human mast cells and only the T cell-dependent mechanism for the development of basophils of both rodents and humans. The most important cytokine for the T cell-dependent mechanism appears to be interleukin-3, whereas for the fibroblast-dependent mechanism it appears to be the ligand for the c-kit receptor (ie, stem cell factor).
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PMID:Development of mast cells and basophils: processes and regulation mechanisms. 812 82

Two types of human mast cells, which are morphologically similar to skin mast cells and lung mast cells, respectively, can be developed from pluripotent stem cells under different culture conditions. The major growth factor for mast-cell development is c-kit ligand, which induces mastocytosis in vivo. However, this cytokine is not sufficient for full maturation of the cells.
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PMID:Development of human mast cells from their progenitors. 829 27

We have subdivided mouse CD4-CD8-CD3- triple-negative (TN) thymocytes into four subsets based upon expression of CD44 and CD25, including CD44+CD25-, CD44+CD25+, CD44-CD25+ and CD44-CD25-. Characterization of these cells revealed several features distinct to each subset, in particular the expression of high levels of c-kit (the receptor for stem cell factor) by CD44+CD25-TN and CD44+CD25+TN but not by CD44-CD25+TN and CD44-CD25-TN. The CD44+CD25+TN subset also included the IL-7 and stem cell factor-responsive cells, whereas only minimal responsiveness was observed by the CD44- populations. These subsets also showed differential cytokine production potential (CD44+CD25- > CD44+CD25+ > CD44-CD25+ > CD44-CD25-) after stimulation with calcium ionophore, PMA and IL-1. The repopulation potential of these subsets in 2-deoxyguanosine-treated fetal thymic lobes supports the following maturation sequence: CD44+CD25- -->CD44+CD25+ -->CD44-CD25+ -->CD44-CD25-. Furthermore, the sequence of progression from CD44+CD25+ to CD44-CD25+ cells was confirmed by their TCR beta-chain gene configuration. The former population exhibits germ-line TCR beta-chain configuration, whereas the latter subset shows a rearranged pattern.
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PMID:A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. 838 91

Scatchard binding analysis has been employed to characterize expression of low-affinity receptors for tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by isolated human placental syncytiotrophoblast microvillous plasma membrane (StMPM) vesicles. Trophoblastic receptors for the c-kit ligand (stem cell factor) could not be identified using the same methods. No high-affinity receptors could be detected for GM-CSF or IFN-gamma, but a minority of high-affinity TNF-alpha receptors were identified. Cross-inhibition studies indicated the low-affinity receptors to be specific for each cytokine rather than to be non-specific cytokine-binding factors. Only relatively high-affinity receptors for TNF-alpha and IFN-gamma could be detected on the BeWo human choriocarcinoma cytotrophoblast cell line, whereas receptor affinity for GM-CSF was similar to that on syncytiotrophoblast. Immunohistochemical staining has confirmed expression of IFN-gamma receptor by syncytiotrophoblast: in contrast, staining for the established TNF-R1 and TNF-R2 receptors was associated mainly with placental vascular endothelium. These low-affinity cytokine receptors could reflect unique biological responses of foetal syncytiotrophoblast in the presence of local concentrations of maternal cytokine.
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PMID:Low-affinity receptors for tumour necrosis factor-alpha, interferon-gamma and granulocyte-macrophage colony-stimulating factor are expressed on human placental syncytiotrophoblast. 840 76

Stem cell factor (SCF) is a cytokine which plays an important role in the development of precursor cells. We have investigated the expression of SCF and its receptor, the c-kit proto-oncogene, in human colorectal carcinoma cell lines. Using reverse transcription-PCR, we confirmed the expression of c-kit in two lines (LS174T and LS1034) and of SCF in 9 of 11 cell lines tested. In a Northern blot, a single transcript of 6.6 kb was detected for SCF mRNA. In addition, two lines (LS174T and HT29) synthesized SCF protein, as detected by Western blot analysis. SCF stimulated proliferation and colony formation of LS174T in a dose-dependent manner up to 160%. A half-maximal effect was obtained with about 5.5 ng/ml of SCF under both growth conditions. LS174T cells expressed the M(r) 145,000 c-kit protein on the cell surface and a neutralizing anti-c-kit mAb inhibited colony formation of LS174T by 40%. Interleukin 4 (IL-4) completely inhibited SCF-induced proliferation of LS174T cells. Interestingly, IL-4 induced an almost complete down-regulation of both c-kit and SCF expression in LS174T. Our findings suggest that in LS174T cells, an SCF-mediated autocrine loop is functional and that IL-4 down-regulates the expression of both the receptor and the ligand of this circuit.
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PMID:Interleukin 4 down-regulates expression of c-kit and autocrine stem cell factor in human colorectal carcinoma cells. 851 88

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

We present a detailed analysis of cytokine expression patterns of the two permanent human bone marrow stromal cell lines, L87/4 and L88/5. These cell lines, previously established in our laboratory, are highly radiotolerant without cell detachment and support long-term cultures of CD(34+)-enriched human cord blood cells. RT-PCR analysis of 22 different cytokines or cytokine receptor mRNAs showed an almost identical expression pattern in the two stromal cell lines compared to primary human Dexter-type stroma. Since stromal feeder lines employed in long-term cultures usually are irradiated and grown in media containing corticosteroids, we analyzed the impact of irradiation and dexamethasone on cytokine production in the two cell lines by RT-PCR, Northern blot analysis, bioassays, and RIAs. By RT-PCR analysis, constitutive mRNA expression of c-kit, G-CSF, GM-CSF, IL-1 beta, IL-6, IL-7, IL-8, IL-11, Kit ligand (KL), LIF, M-CSF, MIP-1 alpha, TGF-beta, and TNF-alpha was demonstrated in both cell lines, with L87/4 a more potent cytokine producer than L88/5. Northern blot data showed an increase in mRNA levels for GM-CSF, IL-1 beta, and LIF by irradiation and IL-1 alpha treatment in both cell lines. IL-1 alpha-induced GM-CSF, IL-1 beta, IL-6, IL-11, and LIF mRNA levels were reduced by the addition of dexamethasone, whereas dexamethasone had no influence on the amounts of IL-1 alpha-induced G-CSF mRNA. L87/4 and, to a lower extent, L88/5 cells showed dexamethasone-dependent increases in KL mRNA, while KL mRNA levels were not stimulated by IL-1 alpha.
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PMID:Constitutive and modulated cytokine expression in two permanent human bone marrow stromal cell lines. 853 85

Interleukin-11 is a stromal cells derived cytokine which stimulates the proliferation of primitive haemopoietic progenitor cells. For this paper we have studied the constitutive expression of IL-11 mRNA in a panel of wellknown leukaemic cell lines and samples from AML patients at diagnosis. Moreover, the same cellular populations were evaluated for their proliferative response to recombinant-human-(r-hu). IL-11 alone and combined with r-hu-IL-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and stem cell factor (SCF, c-kit ligand). The colony-forming ability of HL60, K562, KG1 cells and eight fresh AML cell populations was assessed by a clonogenic assay in methylcellulose. In eight additional AML cases the number of S-phase leukaemic cells induced by IL-11 was determined by the bromodeoxyuridine (BRDU) incorporation assay after 3d of liquid culture. IL-11, as single cytokine, did not stimulate the colony formation of the three myeloid cell lines under serum-containing and serum-free conditions. In contrast, the proliferation of the leukaemic cells in response to IL-3, GM-CSF and SCF was enhanced by co-incubation with IL-11, and this effect was reversed in blocking experiments by the anti-IL-11 Moab. When tested on primary AML samples, IL-11 alone showed little, if any, proliferative activity. However, it increased the IL-3-dependent blast colony formation in eight out of eight cases and GM-CSF in seven cases. IL-11 also augmented synergistically the number of CFU-L stimulated by SCF in seven cases. A combination of three factors (IL-11, SCF and IL-3) yielded optimal colony formation. The BRDU studies showed the significant increase of AML cells in S-phase when IL-11 was combined with SCF, whereas the two CSF had no activity on their own. Positive interaction was also observed when IL-11 was added to IL-3 supplemented cultures in five out of eight cases tested. Reverse transcriptase-polymerase chain reaction amplification (RT-PCR) demonstrated the constitutive expression of IL-11 mRNA in all the cell lines and 11/12 AML samples studied at diagnosis. These results indicate that IL-11 is expressed in leukaemic myeloid cells and that their proliferation is regulated by the cytokine which acts as a synergistic factor.
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PMID:Interleukin-11 (IL-11) acts as a synergistic factor for the proliferation of human myeloid leukaemic cells. 854 68

Flt3 is a class III tyrosine kinase receptor expressed on primitive human and murine hematopoietic progenitor cells (HPC). In previous studies using stroma-free short term assays, Flt3 ligand (FL) has been shown to induce proliferation of HPC at proportions similar to or less than c-kit ligand (steel factor, SF). Using long term stromal cocultivation assays, we studied the effects of FL on proliferation and differentiation of a highly primitive and cytokine nonresponsive subpopulation of human HPC, CD34+cd38- cells. Cell Proliferation was significantly greater with FL than with SF, when used individually or in combinations with interleukin-3 (IL-3) and/or IL-6. The effect of FL was greater on bone marrow (BM) CD34+CD38- cells than the more cytokine responsive cord blood CD34+CD38- cells. Little or no effect was seen with FL on more mature CD34+CD38+ cells from either BM or cord blood. The frequency of colony-forming units (CFU) and high proliferative potential-colony forming cells (HPP-CFC) during early culture ( < or = 30 days) was increased by both SF and FL to similar levels. However, in the LTC-IC period (35 to 60 days) and extended long-term culture initiating cell (ELTC-IC) period ( > 60 days), the frequency of CFU and HPP-CFC was significantly greater in cultures containing FL than those without FL (P < .0025). Fluorescence-activated cell sorter analysis of cultures after 21 days showed a significantly higher percentage of cells remained CD34+ in the combination of FL, IL-3, IL-6, and SF (F/3/6/S) than in 3/6/S (0.78% +/- 0.52% v 0.21% +/- 0.29% respectively, mean +/- SD). Cloning efficiency of BM CD34+CD38- cells was significantly increased by the addition of FL to the combination of 3/6/S (mean 11.7% v 0.5%, P < .0001). These data show that FL is able to induce proliferation of CD34+CD38-cells that are nonresponsive to other early acting cytokines and to improve the maintenance of progenitors in vitro.
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PMID:Flt3 ligand induces proliferation of quiescent human bone marrow CD34+CD38- cells and maintains progenitor cells in vitro. 861 78


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