Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mouse mast cell protease granule tryptases designated mMCP-6 and mMCP-7 are encoded by highly homologous genes that reside on chromosome 17. Because these proteases are released when mast cells are activated, we sought a basis for distinctive functions by examining their fates in mice undergoing passive systemic anaphylaxis. 10 min-1 h after antigen (Ag) was administered to immunoglobulin (Ig)E-sensitized mice, numerous protease/proteoglycan macromolecular complexes appeared in the extracellular matrix adjacent to most tongue and heart mast cells of normal BALB/c mice and most spleen and liver mast cells of V3 mastocytosis mice. These complexes could be intensively stained by anti-mMCP-6 Ig but not by anti-mMCP-7 Ig. Shortly after Ag challenge of V3 mastocytosis mice, large amounts of properly folded, enzymatically active mMCP-7 were detected in the plasma. This plasma-localized tryptase was approximately 150 kD in its multimeric state and approximately 32 kD in its monomeric state, possessed an NH2 terminus identical to that of mature mMCP-7, and was not covalently bound to any protease inhibitor. Comparative protein modeling and electrostatic calculations disclosed that mMCP-6 contains a prominent Lys/Arg-rich domain on its surface, distant from the active site. The absence of this domain in mMCP-7 provides an explanation for its selective dissociation from the exocytosed macromolecular complex. The retention of exocytosed mMCP-6 in the extracellular matrix around activated tissue mast cells suggests a local action. In contrast, the rapid dissipation of mMCP-7 from granule cores and its inability to be inactivated by circulating protease inhibitors suggests that this tryptase cleaves proteins located at more distal sites.
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PMID:Fate of two mast cell tryptases in V3 mastocytosis and normal BALB/c mice undergoing passive systemic anaphylaxis: prolonged retention of exocytosed mMCP-6 in connective tissues, and rapid accumulation of enzymatically active mMCP-7 in the blood. 906 23

Human mast cell precursors arise in the bone marrow and circulate to different tissue microenvironments, where they develop distinct phenotypes that may be characterized by differential expression of the serine protease, chymase. The growth and development of mast cells is stimulated by mast cell growth factor, which is also known as kit ligand because its obligate receptor is KIT, the protein product of the c-KIT proto-oncogene. The in vivo influence of the KIT-kit ligand axis on the phenotype of human mast cells has not been determined. We used immunohistochemistry to detect in situ expression of tryptase and chymase by mast cells of a patient with urticaria pigmentosa and aggressive systemic mastocytosis, whose pathologic mast cells are clonally derived and chronically stimulated by KIT because they all contain the same point mutation causing constitutive activation of KIT. Mast cells in both spleen and skin expressed tryptase, but only in the skin did a majority of mast cells express chymase. We conclude that chronic stimulation of the KIT-kit ligand axis does not irrevocably commit mast cells to a chymase-positive or chymase-negative phenotype. These findings suggest that factors other than kit ligand predominate in determining mast cell phenotype.
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PMID:Chronically KIT-stimulated clonally-derived human mast cells show heterogeneity in different tissue microenvironments. 945 20

Human mast cells (MC) were derived from umbilical cord blood and bone marrow progenitors cultured in the presence of a conditioned medium from a human mastocytosis cell strain and recombinant human kit ligand (rhKL). KL induced MC of predominantly two immunophenotypes, MC(T) and MC(TC). In contrast, the conditioned medium induced MC subtypes MC(TC) and a third subtype, MC(C), positive for chymase but negative for tryptase. This study clearly demonstrates that a third type of MC, MC(C), can be induced in vitro from normal human progenitors.
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PMID:Conditioned media obtained from a human mastocytosis cell strain induce mast cells expressing chymase but not tryptase from human progenitors. 913 May 52

The case of a 62-year-old man who presented with acute abdominal pain and a widespread tumor involving the retroperitoneum is described. Three weeks after initial presentation, the patient died suddenly of acute cardiac failure with signs of arrhythmia. Autopsy revealed a disseminated tumor with infiltration of the retroperitoneal fat, as well as nodules in the left testis and the right atrium. The tumor cells were reactive for CD45, vimentin, and chloroacetate esterase, but were unreactive with a broad spectrum of antibodies against myelomonocytic and lymphocytic antigens and with antibodies against tryptase and c-kit (CD117), which are characteristic markers for mast cells. However, the bone marrow exhibited the typical picture of mastocytosis, with disseminated clusters of differentiated spindle-shaped cells that stained strongly for tryptase, c-kit, and chloroacetate esterase. No infiltrates of well-differentiated mastocytosis could be detected in any of the extramedullary tissues investigated. A diagnosis of bone marrow mastocytosis with an associated undifferentiated extramedullary tumor of hemopoietic origin was established. By definition, the extramedullary tumor could not be diagnosed as a granulocytic sarcoma or (differentiated) mastocytoma, but the possibility that a mast cell progenitor could be involved in the evolution of both tumors cannot be ruled out.
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PMID:Bone marrow mastocytosis associated with an undifferentiated extramedullary tumor of hemopoietic origin. 914 Mar 15

We report a case of bullous mastocytosis in a 30-month-old girl, who developed disseminated pruritic urticarial and bullous lesions on the trunk accompanied by episodes of vomiting and generalized flushing. Her problems began at the age of 6 months. Her stool was repeatedly positive for occult blood. Histamine and 5-hydroxytryptamine were measured in the urine and serum; urine 5-hydroxytryptamine levels were elevated. In addition, trypsin and chymotrypsin levels were raised in the blister fluid. Metachromatic staining of the mast cells in a skin biopsy specimen confirmed the diagnosis. A combination of oral disodium cromoglycate and ketotifen produced a dramatic improvement of the cutaneous and gastrointestinal features.
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PMID:[Bullous mastocytosis in a child]. 917 60

Because in humans mast cells and basophils tend to possess nonsegmented and segmented/multi-lobular nuclei, respectively, nuclear morphology has been a major criterion for assessing the lineage of metachromatic cells of hematopoietic origin. Immature metachromatic cells with mono- and multi-lobular nuclei were both obtained when bone marrow cells from BALB/c mice were cultured for 3 weeks in the presence of interleukin-3. Analogous to the indigenous mature mast cells that reside in the peritoneal cavity and skin, both populations of in vitro-derived cells expressed the surface receptor c-kit, the chymase mouse mast cell protease (mMCP) 5, the tryptase mMCP-6, and the exopeptidase carboxypeptidase A (mMC-CPA). Immunogold electron microscopy confirmed the granule location of mMC-CPA and mMCP-6 in both populations of cells, and cytochemical analysis confirmed the presence of chymotryptic enzymes in the granules. Because mature mast cells possessing multi-lobular nuclei also were occasionally found in the skeletal muscle and jejunum of the BALB/c mouse, the V3 mouse mast cell line was used to investigate the developmental relationship of mast cells that have very different nuclear structures. After the adoptive transfer of V3 mast cells into BALB/c mice, v-abl-immortalized mast cells with mono- and multi-lobular nuclei were detected in the lymph nodes and other tissues of the mastocytosis mice that expressed c-kit, mMCP-5, mMCP-6, and mMC-CPA. These studies indicate that mouse mast cells can exhibit varied nuclear profiles. Moreover, the nuclear morphology of this cell type gives no insight as to its protease phenotype or stage of development.
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PMID:Mouse mast cells that possess segmented/multi-lobular nuclei. 920 74

The effects of recombinant human granulocyte CSF (rhG-CSF) and recombinant human granulocyte-macrophage CSF (rhGM-CSF) on the recombinant human stem cell factor (rhSCF)-dependent development of human mast cells from fetal liver progenitors were examined. Mast cells were identified by immunohistochemical staining for tryptase and by flow cytometric analysis of surface Kit expression. Only rhGM-CSF affected mast cell development. When rhGM-CSF (1, 10, or 100 ng/ml) and rhSCF (50 ng/ml) were added to cell cultures from day 0, both the percentage and absolute numbers of mast cells were diminished after 4 wk compared with cultures exposed to rhSCF alone. Half of the maximal response was achieved at a dose of rhGM-CSF between 0.1 and 1 ng/ml. The Kit+ cells developing in the presence of rhGM-CSF and rhSCF exhibited an intensity of surface Kit expression comparable to that of cells exposed to rhSCF alone. Also, if the initial exposure to rhGM-CSF was delayed for 1 to 3 wk, attenuation of mast cell development waned. These findings are consistent with uncommitted progenitor cells being diverted to nonmast cell lineages by rhGM-CSF, while cells committed to a mast cell lineage, albeit immature, appear to be resistant to the lineage directives of rhGM-CSF. Exposure of fetal liver cells to rhGM-CSF for 1 to 3 days before addition of rhSCF further diminishes the number of mast cells that develop compared with the simultaneous addition of these growth factors on day 0. Whether administration of rhGM-CSF to humans before or together with rhSCF diminishes the mast cell hyperplasia that occurs with rhSCF alone remains to be determined.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor (CSF), but not recombinant human granulocyte CSF, down-regulates the recombinant human stem cell factor-dependent differentiation of human fetal liver-derived mast cells. 921 2

The case of a 63-year-old man with a widespread retroperitoneal tumor and two tumor nodules in the left testis is described. Histopathological and cytopathological examination of tissue from the retroperitoneal tumor led to a diagnosis of lymphoreticular neoplasia. The patient died in acute cardiac failure, five weeks after initial presentation. Autopsy revealed another tumor nodule in the right atrium. Macroscopically, the bone marrow appeared normal. The tumor cells were reactive for CD45, vimentin and chloroacetate esterase, but were uncreative with a broad spectrum of antibodies against myelomonocytic and lymphocytic antigens and antibodies against tryptase and c-kit (CD117), characteristic markers for mast cells. However, the bone marrow exhibited the typical picture of mastocytosis. A diagnosis of bone marrow mastocytosis with an associated secondary extramedullary mast cell sarcoma was established. The cause of death was heart failure due to arrhythmia caused by an exophytic atrioseptal tumor nodule.
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PMID:[Association of bone marrow mastocytosis with extremely immature extramedullary mast cell sarcoma]. 927 45

Mast cells are the primary effector cells of immediate hypersensitivity reactions in humans. Upon mast cell activation both preformed and newly synthesized mediators are secreted. Histamine can be measured by fluorometric assays, radioenzymatic assays, and immunoassays. These methods have been applied to plasma and urine to detect histamine that had been released in vivo and to release histamine in vitro from basophils and mast cells. Another mast cell constituent is tryptase, which is a more selective marker of mast cells, because negligible amounts are found in basophils. beta-Tryptase is stored in secretory granules and is actively released when mast cells degranulate. alpha-Protryptase remains in the proenzyme form and is constitutively released from mast cells, and consequently its level in serum reflects total numbers of mast cells. alpha-Protryptase levels are elevated in serum at baseline in subjects with systemic mastocytosis, whereas beta-tryptase is elevated in serum from subjects with systemic anaphylaxis. These markers serve as precise clinical indicators of the involvement of mast cells in human disease.
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PMID:Markers of mast cell degranulation. 928 67

Systemic mast cell disease/mastocytosis (SMCD) is best defined as a multitopic proliferation of cytologically and/or functionally abnormal tissue mast cells (TMC). SMCD preferentially involves the bone marrow, skin, spleen, liver, and lymph nodes. The histopathological diagnosis of SMCD may be very difficult to make, and the disease is often not considered in the differential diagnosis of lymphoreticular neoplasia. In suspected cases of SMCD, basic dyes such as Giemsa and toluidine blue are useful to demonstrate the specific metachromatic granules of TMC. The naphthol AS-D chloroacetate esterase reaction has also proved to be very reliable for enzyme-histochemical identification of TMC. Major diagnostic problems may arise in cases of malignant or "aggressive" SMCD exhibiting tissue infiltrates consisting predominantly of highly atypical, non-metachromatic TMC, which are usually also only weakly reactive for chloroacetate esterase. Immunostaining with antibodies against the mast cell-specific proteases tryptase and chymase has proved to be of great value of establishing the correct diagnosis in such cases. Anti-tryptase antibodies have major diagnostic significance due to their extremely high sensitivity and specificity. The classification of SMCD is controversial, but there is increasing support for the differentiation of at least two major subtypes that differ in prognosis: (i) a benign or "indolent" variant in which skin involvement (urticaria pigmentosa-like skin lesions) is usual, but associated malignant hematological disorders are rare; and (ii) a malignant or "aggressive" variant where skin involvement is usually absent but concomitant malignant hematological disorders (myelodysplastic and myeloproliferative syndromes and acute non-lymphocytic leukemias) are very common. Preliminary molecular biological studies of a few cases of malignant SMCD using the recently developed HUMARA assay have yielded evidence that the disease is monoclonal.
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PMID:Systemic mast cell disease (mastocytosis). General aspects and histopathological diagnosis. 930 69


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