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

Polycationic mast cell activators, such as compound 48/80 and substance P, have been reported to activate connective tissue-type mast cells specifically by interacting directly with the Gi family of trimeric GTP-binding protein. We now demonstrate that mouse bone marrow-derived mast cells (BMMC) developed in IL-3, an immature mast cell population lacking responsiveness to the Gi-coupled polycationic mast cell activators, underwent maturation toward a connective tissue-type mast cells-like phenotype that responded to polycationic compounds after only 4 to 6 days of coculture with Swiss 3T3 fibroblasts in concert with recombinant soluble c-kit ligand (KL), whereas 3T3 or KL alone was insufficient to mediate this process. Under optimal conditions, cocultured BMMC released approximately 30% beta-hexosaminidase and generated approximately 1 ng of PGD2/10(6) cells within a few minutes in response to compound 48/80 or substance P. Furthermore, these cells expressed cytokines, such as IL-1beta and IL-6, and PG endoperoxide synthase-2 1 to 4 h after stimulation with compound 48/80 or substance P. All these responses were suppressed effectively by pertussis toxin, implicating functional Gi coupling. Regardless of the remarkable change in polycationic compound sensitivity, there was only a minimal change in the constitutive expression of Gi3 alpha after coculture. These results together with the observation that before coculture BMMC responded to thrombin through its Gi-coupled receptor suggest that the alteration in a certain step(s) distinct from the level of Gi3 alpha protein expression is important for the acquisition of responsiveness to the polycationic compounds by the synergistic action of KL and 3T3 fibroblast-derived factor. Several lines of evidence have revealed that 3T3-derived factor appears to differ from the known cytokines, prostanoids, and adhesion molecules and is a labile soluble substance.
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PMID:Mouse bone marrow-derived mast cells undergo exocytosis, prostanoid generation, and cytokine expression in response to G protein-activating polybasic compounds after coculture with fibroblasts in the presence of c-kit ligand. 897 15

Congenital amegakaryocytic thrombocytopenia (CAMT) is an uncommon disorder in newborns and infants, characterized by isolated thrombocytopenia and megakaryocytopenia in the first year without physical anomalies. The defect of thrombopoiesis is not well understood. Recently, thrombopoietin (TPO), the ligand for the c-mpl receptor, was cloned. Accumulating evidence from in vitro and in vivo studies indicate that TPO plays a key role in the regulation of megakaryocytopoiesis. In this study we examined the effect of TPO on megakaryocyte colony formation from a patient with CAMT using a plasma-containing methylcellulose clonal culture. The in vitro results demonstrated a defective response to TPO in megakaryocyte colony formation from bone marrow mononuclear cells (MNC) of the patient. although interleukin-3 (IL-3) but not stem cell factor (SCF) induced only a small number of megakaryocyte colonies. These findings indicated that thrombocytopenia in CAMT could not be corrected by administration of TPO in vitro. Additionally, clonal cultures containing SCF, IL-3, IL-6 and erythropoietin showed decreased numbers of erythroid and myelocytic progenitors in the bone marrow of the patient. The serum TPO level measured by enzyme-linked immunosorbent assay was significantly higher than that in healthy controls. By PCR, marrow MNC from healthy children and from a patient with essential thrombocytosis expressed c-mpl mRNA, whereas no c-mpl mRNA was detected in marrow MNC from the patient with CAMT. There was no difference in the CD34 expression and c-kit mRNA between the CAMT patient and healthy children. The results of this study suggest that the pathophysiology in CAMT may be a defective response to TPO in haemopoietic cells through impaired expression of c-mpl mRNA.
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PMID:Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia. 902 14

Efficient expansion of hematopoietic progenitor cells requires, at least, the simultaneous stimulation of the receptors c-kit and gp130. While c-kit is activated by SCF; gp130, in cells which do not express sufficient amounts of IL-6R, can be activated by the complex of soluble IL-6R (sIL-6R) and IL-6. The therapeutic use of IL-6/sIL-6R, however, has been hampered by the high concentrations of the sIL-6R protein required. We have designed a fusion protein of sIL-6R and IL-6, linked by a flexible peptide chain, that was expressed to high levels. On gp130 expressing cells the fusion protein turned out to be fully active at 100 to 1,000-fold lower concentration than the combination of unlinked IL-6 and IL-6R. The fusion protein was used to effectively expand human hematopoietic progenitor cells ex vivo in a dose dependent fashion.
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PMID:I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. 903 38

We have investigated the mechanisms by which hematopoiesis is suppressed in patients suffering from human cytomegalovirus (HCMV) infections. Mixed populations of human bone marrow stromal and hematopoietic progenitor cells were inoculated with the Towne strain of HCMV to determine whether these populations could be infected and support HCMV replication. We found that the Towne strain of HCMV was capable of infecting and replicating in a mixed population of bone marrow stromal cells. We observed no significant alterations in bone marrow stromal cell proliferation or the production of IL-6, GM-CSF, soluble c-kit ligand and TNF-alpha following HCMV replication in either stimulated lipopolysaccharide (LPS) or unstimulated conditions. In samples of culture supernatants from LPS-stimulated HCMV-infected stromal cells, significant elevations in MIP-1alpha were observed. TGF-beta1 levels on the other hand exhibited two patterns following HCMV exposure; either TGF-beta1 levels decreased regardless of LPS stimulation or there was no effect. In addition, we observed that exposure to the Towne strain of HCMV resulted in significant inhibition of both granulocytic and erythrocytic colony formation in methylcellulose progenitor assays. Thus, both the direct effect of HCMV on hematopoietic progenitors as well as altered cytokine production by bone marrow stromal cells (including MIP-1alpha and TGF-beta1, but not IL-6) could contribute to hematopoietic failure during HCMV infection.
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PMID:Infection and replication of human cytomegalovirus in bone marrow stromal cells: effects on the production of IL-6, MIP-1alpha, and TGF-beta1. 905 14

Mast cells are a heterogeneous family of immune cells that, when activated through their high affinity IgE receptors (Fc epsilonRI), release various granule mediators (e.g., neutral proteases and serglycin proteoglycans) and proinflammatory cytokines (e.g., IL-6 and TNF-alpha). We and others have shown that the growth and differentiation of immature, nontransformed mouse bone marrow-derived mast cells (mBMMC) can be regulated in vitro by IL-3, IL-10, and c-kit ligand. We now report that glucocorticoids inhibit the c-kit ligand- and IL-3-induced proliferation of mBMMC, the Fc epsilonRI-mediated expression of TNF-alpha, and the IL-10-mediated expression of the two chymases designated mouse mast cell protease (mMCP)-1 and mMCP-2. In contrast, glucocorticoids induce mBMMC to increase their expression of serglycin proteoglycan and carboxypeptidase A. As assessed by nuclear run-on and RNA blot analyses, dexamethasone inhibited the IL-10-mediated expression of mMCP-1 and mMCP-2, primarily by inducing rapid degradation of their transcripts. The stimulative effect on serglycin proteoglycan expression and the inhibitory effect on chymase expression were dose and time dependent and glucocorticoid specific. These findings indicate that glucocorticoids exert profound and diverse effects on the growth, cytokine expression, and granule differentiation of mouse mast cells, and that at least some of this regulation occurs through a post-transcriptional mechanism.
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PMID:Glucocorticoids inhibit the cytokine-induced proliferation of mast cells, the high affinity IgE receptor-mediated expression of TNF-alpha, and the IL-10-induced expression of chymases. 912 1

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

Thrombopoietin (Tpo) is a primary regulator of megakaryocyte and platelet production. However, studies in c-mpl-deficient mice suggest that Tpo might also play an important role in early hemopoiesis. Here, the direct ability of Tpo to stimulate stroma-independent growth, multilineage differentiation, and progenitor cell expansion from single primitive CD34+ CD38- human bone marrow cells was investigated. Tpo alone stimulated limited clonal growth, but synergized with c-kit ligand (KL), flt3 ligand (FL), or IL-3 to potently enhance clonogenic growth. Whereas KL and FL in combination stimulated the clonal growth of only 3% of CD34+ CD38- cells, 40% of CD34+ CD38- cells were recruited by KL+FL+Tpo, demonstrating that Tpo promotes the growth of a high fraction of CD34+ CD38- progenitor cells. Additional cytokines (IL-3, IL-6, and erythropoietin (Epo)) did not significantly enhance clonal growth above that observed in response to KL+FL+Tpo. In contrast, Tpo enhanced clonogenic growth in response to KL+FL+IL-3+IL-6+Epo by as much as 80%, implicating a key role for this cytokine in early hemopoiesis. Importantly, we also demonstrate that the majority of Tpo-recruited CD34+ CD38- progenitor cells have a multilineage differentiation potential, and that Tpo promotes prolonged expansion of multipotent progenitors. Specifically, whereas progenitor cells were reduced in cultures containing only KL+FL, addition of Tpo resulted in 40-fold expansion of multipotent progenitors following a 14-day incubation. Finally, we identified inhibitors of Tpo-induced progenitor cell growth, in that TGF-beta as well as TNF-alpha almost completely abrogated the growth of CD34+ CD38- progenitor cells in response to Tpo alone as well as KL+FL+Tpo.
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PMID:Thrombopoietin directly and potently stimulates multilineage growth and progenitor cell expansion from primitive (CD34+ CD38-) human bone marrow progenitor cells: distinct and key interactions with the ligands for c-kit and flt3, and inhibitory effects of TGF-beta and TNF-alpha. 916 33

We have been studying hematopoietic effects by the tachykinins, which like many other neuropeptides can be expressed in neural and nonneural tissues. Substance P (SP) and neurokinin-A (NK-A), members of the tachykinins are immune and hematopoietic modulators. SP and NK-A are derived from the preprotachykinin-I gene (PPT-I) through alternate splicing and posttranslational modification. In the bone marrow (BM), nerve fibers provide a source of neural SP and the stroma provides a source of nonneural SP. The tachykinins interact with each of three cloned neurokinin (NK) receptors (NK-1R, NK-2R, NK-3R) with SP and NK-A exhibiting binding preferences for NK-1R and NK-2R, respectively. Proliferation of myeloid progenitors (CFU-GM) is differentially regulated by SP and NK-A. The former enhances the proliferation whereas the latter is inhibitory. The BM stroma mediates most of the hematopoietic effects exerted by SP and NK-A partly through the induction of cytokines. The proliferative effects of SP correlate with the induction of positive hematopoietic growth factors such as IL-3, IL-6, GM-CSF and c-kit ligand and the inhibitory effects by NK-A correlate with the induction of two negative hematopoietic regulators, MIP-1 alpha and TGF-beta. Intracellular signals mediated by NK-1R and NK-2R are part of the mechanism responsible for tachykinin-mediated regulation of hematopoiesis. The stimulatory effects on BM progenitors mediated by NK-1R can be partly inhibited by NK-2R activation. IL-1 and other cytokines induced by SP in BM stroma modulate NK-1R induction. Furthermore, SP can induce IL-1 type I receptor in stroma. Together, these data suggest that the tachykinins and the cytokines interact to regulate hematopoiesis. These interactions contribute to hematopoietic regulation by mechanisms that involve induction of: (1) tachykinins and cytokines by each other; (2) NK-1R by cytokines and (3) cytokine receptor by the tachykinins. These studies emphasize that in terms of hematopoiesis, the cytokines and neuropeptides are not mutually exclusive factors and thus, the hematopoietic regulatory network would be incomplete without the role of neuropeptides being considered.
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PMID:Hematopoietic modulation by the tachykinins. 928

We recently showed that c-kit signal synergizes with glycoprotein (gp)130 signal mediated by a complex of interleukin (IL)-6 and soluble IL-6 receptor (IL-6/sIL-6R) to stimulate the expansion of human primitive hematopoietic progenitor cells and erythropoietin-independent erythropoiesis. In the present study, we examined the effect of a ligand for Flt3 (FL), whose receptor tyrosine kinase is closely related to c-kit, in combination with IL-6/sIL-6R on human hematopoiesis in vitro. In serum-containing methylcellulose clonal culture of cord blood CD34(+) cells, whereas FL alone stimulated only granulocyte-macrophage (GM) colony formation, erythroid bursts and mixed colonies in addition to GM colonies were induced by FL with IL-6/sIL-6R, but not IL-6/sIL-6R alone. In suspension culture, CD34(+) cells generated a small number of myeloid cells in the presence of FL or IL-6/sIL-6R alone. However, the addition of IL-6/sIL-6R to the culture with FL induced the generation of a significant number of erythroid cells and megakaryocytes in addition to myeloid cells. The combination of FL and IL-6/sIL-6R also induced a remarkable expansion of GM colony- and erythroid burst-forming cells and multipotential progenitors, although FL or IL-6/sIL-6R alone induced the generation of only a small number of progenitors for GM colonies. The synergistic effects of FL and IL-6/sIL-6R were confirmed in serum-free clonal and suspension cultures. In addition, the addition of anti-human gp130 monoclonal antibodies abrogated the synergistic action. These results indicate that Flt3 signal, as well as c-kit signal, synergizes with gp130 signal to stimulate human myelopoiesis, erythropoiesis and megakaryopoiesis, and the expansion of primitive multipotential hematopoietic progenitor cells.
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PMID:Synergistic action of Flt3 and gp130 signalings in human hematopoiesis. 937 47

We assessed the biologic role of signaling through gp130, a signal-transducing receptor (R) component, in human hematopoiesis in vitro. Although peripheral blood-derived CD34(+) cells ubiquitously expressed gp130 and interleukin-3 receptor alpha (IL-3Ralpha), IL-6Ralpha was only detected on 80% of these CD34(+) cells. We sorted CD34(+)IL-6R+ or CD34(+)IL-6R- cells and studied the effect on hematopoietic colony formation of signaling through gp130 activated by IL-6 or a combination of IL-6 and recombinant soluble human IL-6R (sIL-6R) in the presence or absence of stem cell factor (SCF ) and/or IL-3. Signals activated by SCF, IL-6, or IL-6/sIL-6R complex alone did not induce significant colony formation. However, a combination of IL-3, SCF, and IL-6/sIL-6R complex dramatically induced many neutrophil (colony-forming unit-granulocyte [CFU-G]), erythroid burst (burst-forming unit-erythrocyte [BFU-E]), erythrocyte-containing mixed (CFU-Mix), and megakaryocyte (CFU-Meg) colony formations when CD34(+)IL-6R- cells were used as the target. CFU-G colony formation induced by the three signals was more evident when CD34(+)IL-6R+ cells were used as the target. This distinct synergistic effect of the three different signals was confirmed by single-cell clone-sorting experiments. Moreover, colony formation (including CFU-G, BFU-E, CFU-Mix, and CFU-Meg) was observed even in the presence of neutralizing antibodies for granulocyte colony-stimulating factor, erythropoietin, and thrombopoietin (c-Mpl), whereas neutralizing antibodies for gp130, IL-6R, IL-3, and SCF partially or completely blocked the synergistic effect. The maturation of neutrophilic, erythroid, and megakaryocytic cells supported by the three signals in serum-free cultures was confirmed by immunostaining using anti-CD66b, antiglycophorin A, antihemoglobin alpha, and anti-CD41 monoclonal antibodies, respectively. In contrast, any two of the three signals were insufficient for effective blood cell production in the absence of maturation factors. These results suggest that simultaneous activation of the three signals through gp130, c-kit, and IL-3R can induce in vitro proliferation and differentiation of trilineage hematopoietic progenitors in the absence of terminally acting lineage-specific factors.
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PMID:Simultaneous activation of signals through gp130, c-kit, and interleukin-3 receptor promotes a trilineage blood cell production in the absence of terminally acting lineage-specific factors. 938 93


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