[ON THE BEHAVIOR OF PLASMA CELLS AND MAST CELLS OF METASTASIS FREE CERVICAL LYMPH NODES IN LARYNGEAL CARCINOMA].
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Antibody Formation↗
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Fibroblast-dependent growth of mouse mast cells in vitro: duplication of mast cell depletion in mutant mice of W/Wv genotype.
In spite of the apparent depletion of mast cells in tissues of mutant mice of W/Wv genotype, cells with many features of mast cells do develop when bone marrow cells of W/Wv mice are cultured in the presence of pokeweed mitogen-stimulated spleen cell-conditioned medium (PWM-SCM). In order to resolve this discrepancy and facilitate the analysis of the W mutation, we attempted to establish an in vitro system in which the in vivo defect of W/Wv mice can be reproduced. Cultured mast cells (CMC) were developed from bone marrow cells of either W/Wv or congenic +/+ mice, and then co-cultured with NIH/3T3 mouse fibroblasts in media supplemented only with fetal calf serum (i.e., in the absence of PWM-SCM). Under this condition, CMC from +/+ mice continued to divide and were maintained for more than 4 weeks. The supportive effect of NIH/3T3 cells required close-range interactions with CMC and was not due to synthesis of the known mast cell growth factors, interleukins 3 and 4. By contrast, CMC from W/Wv mice were not maintained, and the number of mast cells remaining after 4 weeks of co-culture was only 1% of the normal +/+ counterparts. Thus, the humoral factor-independent and cell contact-dependent system presented here revealed the intrinsic defects in growth and differentiation of CMC derived from W/Wv mice and might be useful for biochemical and molecular analysis of the gene product(s) encoded at the W locus.
Animals↗
Loss of flk-2/flt3 expression during commitment of multipotent mouse hematopoietic progenitor cells to the mast cell lineage.
The expression of c-kit and flk-2/flt3 was analyzed in various stages of mast cell differentiation using reverse transcriptase polymerase chain reaction (RT-PCR). Mouse fetal liver cells were sorted using antibodies for Sca-1 (Ly6A/E) and CD43 to obtain a population enriched for early progenitors; committed mast cell progenitors were absent from this population. Mouse fetal liver-derived, IL-3-dependent blast cell colonies provided a source of committed mast cell progenitors, and mast cell colonies provided mature mast cells. Comparison of these populations showed that some uncommitted cells express both c-kit and flk-2/flt3. At the time of commitment to the mast cell lineage, the expression of c-kit increases compared to that of uncommitted progenitors, and the expression of flk-2/flt3 becomes undetectable. Previous studies have shown that steel factor, the ligand for c-kit, supports mast cell differentiation in vivo and in vitro. In contrast, the ligand for flk-2/flt3 is inactive on mast cells. Thus, receptor gene expression appears to be an important determinant of the response or lack of response of mast cells to the ligands for these two homologous receptors.
Animals↗
Mast cell chymase expression and mast cell phenotypes in human rejected kidneys.
BACKGROUND: Mast cells (MCs) are known to participate in various types of chronic disease, but their role in chronic renal rejection is poorly understood. Recently, distinct phenotypes of MCs have been described in humans by the demonstration of one protease, chymase. Hence, we questioned whether chymase in MCs could play a role in the pathogenesis of renal rejection in humans. METHODS: We investigated MC chymase expression and MC phenotypes, using immunohistochemical single- and double-staining techniques, in nephrectomy (N = 13) and biopsy (N = 8) specimens of human rejected kidneys. Tissue chymase levels were determined by enzymatic assay for chymase activity. We also examined the association between MC chymase expression and the degree of interstitial fibrosis in these renal allografts. RESULTS: Based on chymase positivity, rejected kidneys were divided into two groups, a chymase-negative [Chy(-)] group and a chymase-positive [Chy(+)] group. Quantitative analysis showed that the number of chymase-positive MCs and tissue chymase levels were significantly higher in the Chy(+) group than in the Chy(-) group. Furthermore, the interstitial fibrotic area in the Chy(+) group was significantly larger than that in the Chy(-) group. Immunodouble staining analysis also demonstrated that a new MC phenotype, positive for chymase but negative for tryptase, was present in the human rejected kidney. CONCLUSIONS: These results show that increased expression of chymase in MCs is related to the severity of interstitial fibrosis in human rejected kidneys.
Adolescent↗
Stem cell factor influences mast cell mediator release in response to eosinophil-derived granule major basic protein.
Stem cell factor (SCF) is an important mast cell growth, differentiation, and survival factor. We investigated whether SCF influenced the response of mouse mast cells to an IgE-independent stimulus, eosinophil-derived granule major basic protein (MBP). Mouse bone marrow cultured mast cells (BMCMC) were derived in either concanavalin-stimulated mouse spleen conditioned medium (CM) or SCF. The cloned growth, factor-independent mast cell line Cl.MC/C57.1 was also studied. BMCMC in SCF exhibited cytochemical staining properties, protease and histamine content, and increased serotonin uptake consistent with more mature differentiated mast cells as compared with BMCMC in CM or Cl.MC/ C57.1 cells. BMCMC in SCF released serotonin, 14C-labeled arachidonic acid metabolites and tumor necrosis factor-alpha (TNF-alpha) on stimulation with MBP, while no response was seen from either BMCMC in CM or Cl.MC/C57.1 cells. All three mast cell populations released mediators on stimulation with the cationic MBP analog, poly-L-arginine, indicating that the cationic charge did not explain the selective response of BMCMC in SCF to eosinophil-derived granule MBP. These findings show that SCF significantly influences mast cell differentiation and the responsiveness of mast cells to eosinophil-derived granule MBP.
Animals↗
Localization of protease-activated receptors-1 and -2 in human mast cells: indications for an amplified mast cell degranulation cascade.
Protease-activated receptors (PARs) belong to a family of G-coupled seven transmembrane receptors that are activated by a proteolytic cleavage of their N-termini. Recent studies suggest the involvement of protease-activated receptors-1 and -2 (PAR-1, PAR-2) activators in mast cell degranulation in various physiological and pathophysiological processes in inflammatory responses. Although PAR-1 and PAR-2 activating proteases, thrombin and tryptase, have been associated with mast cell activation, PAR-1 and PAR-2 have not been localized within these cells. We describe here the localization of PAR-1 and PAR-2 in mast cells from various normal human tissues using immunohistochemical and double immunofluorescence techniques. The presence of these receptors on the membrane may explain the actions of accessible extracellular thrombin and tryptase for mast cell activation. In addition to the membrane labeling, these receptors are also localized on the membrane of the intracellular tryptase-positive granules, which may function to sustain further mast cell degranulation upon exocytosis. The localization of these two receptors in mast cells suggests a novel mechanism for controlling mast cell activation through regulation of PAR-1 and PAR-2.
Cell Degranulation↗
The role of mast cells in demyelination. 1. Myelin proteins are degraded by mast cell proteases and myelin basic protein and P2 can stimulate mast cell degranulation.
Incubation of bovine peripheral myelin with supernatants from degranulated rat serosal mast cells led to extensive loss of P0. Similarly, when myelinated axons prepared from guinea pig CNS were incubated with degranulation supernatants, a significant loss of basic protein (MBP) was observed. As cationic peptides can stimulate mast cell degranulation, rat serosal mast cells were incubated with MBP, and with P2. Degranulation was assayed by measurement of release of the granule enzyme beta-hexosaminidase and it was found that both MBP and P2 stimulated 40-50% degranulation at a concentration of 50 micrograms/ml. The results of this study suggest that release of mast cell proteases could contribute to myelin damage in both the PNS and CNS, and that subsequent release of P2 or MBP or their breakdown products could potentiate further mast cell degranulation.
Animals↗
Stem cell factor induces mast cell adhesion to fibronectin.
Stem cell factor (SCF) or c-kit ligand is a growth factor cytokine produced by stromal cells that is known to influence mast cell proliferation and differentiation. We hypothesized that SCF may also influence the adhesion of mast cells to connective tissue matrix. To examine this hypothesis, we stimulated MCP5/L mast cells or murine bone marrow-derived cultured mast cells (BMCMC) with either SCF or PMA and observed adhesion to fibronectin (FN). As expected, 80 to 90% of PMA-activated MCP5/L cells or BMCMC adhered to FN. In addition, SCF promoted MCP5/L cell or BMCMC adhesion to FN in a dose-response fashion with 50 to 60% of BMCMC adhering to FN at a concentration 10 ng/ml of SCF. BMCMC adhesion was observed with as little as 200 pg/ml of SCF. Adhesion of SCF stimulated BMCMC to FN did not require IL-3, but was dependent on the concentration of FN used to coat the assay surface. Mast cell adhesion in the presence of SCF appeared to occur through an integrin receptor as adhesion was calcium dependent and could be blocked by an RGD (Ang, Gly, Asp)-containing peptide. SCF did not directly mediate adhesion through interaction with c-kit, as FN-coated surfaces exposed to SCF before initiation of the adhesion assay did not promote adhesion in the absence of soluble SCF. Rather, SCF appeared to stimulate adhesion to FN by activating mast cells through its interaction with c-kit. Thus, antibody to SCF blocked adhesion, and rat and murine SCF stimulated BMCMC adhesion to FN, but human SCF, which does not bind to murine c-kit, did not stimulate adhesion. Genistein, which inhibits tyrosine kinase activity, partially inhibited SCF-induced adhesion. SCF thus stimulates mast cell adhesion and, because SCF is produced normally in tissues, it may be a major factor responsible for the adhesion of mast cells to connective tissue matrix under physiologic conditions.
Amino Acid Sequence↗
Mast cell heterogeneity in the gastrointestinal tract: variable expression of mouse mast cell protease-1 (mMCP-1) in intraepithelial mucosal mast cells in nematode-infected and normal BALB/c mice.
Soluble granule chymases in rodent intestinal mucosal mast cells (IMMCs) may play an important role in altering epithelial permeability during immediate hypersensitivity reactions. Using a monoclonal antibody against the chymase mouse mast cell protease-1 (mMCP-1), we have shown that it is constitutively expressed in < or = 20% of esterase-positive (esterase+) IMMCs but not in esterase+ gastric mucosal mast cells (GMMCs) in normal BALB/c mice. Intestinal infection with mouse- or rat-adapted strains of Nippostrongylus brasiliensis resulted in IMMC hyperplasia with 100% of esterase+ IMMCs expressing mMCP-1. In contrast, there was a variable response in terms of numbers of GMMCs and of the proportion expressing mMCP-1. Esterase+ mast cells in the gastric submucosa, muscularis, ear pinna, lung parenchyma, major airway submucosa, and peritoneal cavity did not express mMCP-1. The few airway esterase+ mast cells expressing mMCP-1 were, like the great majority of IMMCs and GMMCs, located intraepithelially. In conclusion, mMCP-1 is predominantly expressed by intraepithelial mucosal mast cells but not in all sites; the immunological stimulus associated with intestinal nematodiasis substantially up-regulates mMCP-1 expression by mast cells in the jejunum but not in the stomach; IMMCs and GMMCs in BALB/c mice are phenotypically and possibly functionally distinct.
Animals↗
Stimulation of mucin secretion from human bronchial epithelial cells by mast cell chymase.
AIM: To investigate the effect of chymase on the mucin secretion from human bronchial epithelial cells. METHODS: Primarily-cultured human bronchial epithelial (PCHBE) cells and normal human bronchial epithelial (NHBE) cells were cultured with chymase or other stimulus in a mixture of bronchial epithelial growth medium (BEGM) and Dulbecco's modified Eagle's medium (DMEM), and the quantities of stimulatory mucin release were recorded. MUC5AC mucin was measured with an ELISA and dolichos biflorus agglutinin (DBA) mucin was determined with an enzyme linked DBA assay. RESULTS: A dose-dependent secretion of DBA mucin from PCHBE cells was observed with chymase with a maximum secretion of 98 % above baseline being achieved following 3 h incubation. The action of chymase started from 1 h, peaked at 3 h and dramatically decreased at 20 h following incubation. Chymase was able to also stimulate approximately 38 % increase in MUC5AC mucin release from PCHBE cells, and about 121 % increase in DBA mucin release from NHBE cells. A chymase inhibitor soybean trypsin inhibitor (SBTI) was able to inhibit up to 85 % chymase induced mucin release, indicating that the enzymatic activity was essential for the actions of chymase on bronchial epithelial cells. CONCLUSION: Chymase is a potent stimulus of mucin secretion from human bronchial epithelial cells. It can contribute to mucus hypersecretion process in the patients with chronic obstructive pulmonary disease or asthma.
Bronchi↗
Differential expression of CD2 on neoplastic mast cells in patients with systemic mast cell disease with and without an associated clonal haematological disorder.
Recently, aberrant coexpression of CD2 and CD25 has been reported to reliably distinguish neoplastic mast cells from normal or so-called reactive mast cells. Such expression is included in the consensus diagnostic criteria for systemic mast cell disease (SMCD). In our study of patients with SMCD, we found CD2 expression to be more prevalent on mast cells from patients without an associated haematological disorder (P = 0.04). Furthermore, no correlation was found between mast cell CD2 expression and other clinicopathological features in these patients.
Antigens, Neoplasm↗
[Regulation of the cultured mouse parenchymal liver cells (P-LC) by mast cells].
Mast cells suppressed the proliferation of parenchymal liver cells (P-LC) in a dose-dependent manner, when they were cocultured with P-LC. On the contrary, mast cells activated by IgE and anti-IgE enhanced DNA synthesis of P-LC dose-dependently. The activity enhancing the proliferation of P-LC was found in the supernatant of the activated mast cells, but not in that of untreated mast cells, suggesting the secretion of active factors by active mast cells. Histamine, which are released by the activated mast cells, suppressed the enhancement of P-LC proliferation by activated mast cells. Since histamine and heparin did not effect the proliferation of P-LC directly, histamine may bring the suppression through regulating the activated mast cell. On the basis of these findings, we discuss the role of mast cells in liver regeneration.
Animals↗
Cloned mouse mast cells and normal mouse peritoneal mast cells. Determination of serotonin content and ability to synthesize serotonin in vitro.
We determined the serotonin (5-hydroxytryptamine, 5HT) content of growth factor dependent mouse mast cell lines or clones, and measured their ability to synthesize and store 3H-5HT from exogenous 5-hydroxy-[G-3H]-tryptophan (3H-5HTP) in vitro. Mast cells grown in vitro synthesized 3H-5HT from 3H-5HTP at rates equal to or greater than those of peritoneal mast cells freshly isolated from normal mice. Furthermore, under usual conditions of culture, mast cell lines or clones contained more 5HT than freshly isolated peritoneal mast cells.
5-Hydroxytryptophan↗
Immortalization and characterization of human cell lines with mast cell and monocytic properties.
We have previously derived a cell strain which had both mast cell and monocytic properties from the bone marrow of a child with diffuse cutaneous mastocytosis. This cell strain, termed HBM-M, consisted of two cell populations both of which possessed certain ultrastructural, cytochemical and surface phenotypic features of degranulated mast cells. The cells also displayed cytochemical and surface phenotypic features of monocytes. These cells may represent a common bone marrow derived mast cell/monocyte precursor. Studies of human mast cells have been hindered by the fact that it is difficult to establish such cells in long-term culture. Thus, we sought to immortalize HBM-M cells by introducing Simian virus 40 large T-antigen. Following transfection by the strontium phosphate technique, transformed cells were selected, expanded and passaged until the cells entered a non-proliferative phase termed crisis. Certain clones passed through crisis 3 months later and by this means two immortal cell lines, HBM-MI-1 and HBM-MI-2, were obtained. The criterion for immortality was growth for greater than 100 population doublings. The immortal cell lines retained some, but not all, of the mast cell and monocytic properties of the original HBM-M cell strain. The immortalization of the cell strain HBM-M provides an opportunity to investigate the mast cell and monocytic properties of these cells, and the apparent relationship between mast cells and monocytes.
Animals↗
Nitric oxide: a regulator of mast cell activation and mast cell-mediated inflammation.
Nitric oxide (NO) plays diverse roles in physiological and pathological processes. During immune and inflammatory responses, for example in asthma, NO is generated at relatively high and sustained levels by the inducible form of nitric oxide synthase (NOS-2). NOS-2 derived NO regulates the function, growth, death and survival of many immune and inflammatory cell types. In the case of mast cells, NO suppresses antigen-induced degranulation, mediator release, and cytokine expression. The action of NO on mast cells is time dependent, requiring several hours, and noncGMP mediated, most probably involving chemical modification of proteins. NO inhibits a number of mast cell-dependent inflammatory processes in vivo, including histamine mediated vasodilatation, vasopermeation and leucocyte-endothelial cell attachment. In human asthma and animal models of lung inflammation the role of NO is harder to define. However, although there are conflicting data, the balance of evidence favours a predominantly protective role for NO. Mimicking or targeting NO dependent pathways may prove to be a valuable therapeutic approach to mast cell mediated diseases.
Animals↗
1995 Mack-Forster Award Lecture. Review. Mast cell differentiation antigens: expression in normal and malignant cells and use for diagnostic purposes.
Antibodies against haemopoietic differentiation antigens are widely used for the identification and classification of leukaemic cells. Mast cells are distinct haemopoietic cells and express a unique composition of antigens. They can be differentiated from basophils and all other lymphohaemopoietic cells by using antibodies to cell surface receptors and granular mediator molecules. This paper provides evidence that antibodies against mast cell antigens can be used to identify and classify malignant cell populations in patients with mastocytosis.
Antigens, CD↗
Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim.
Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)-only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEK/MAPK) and phosphatidylinositol 3 (PI3)-kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim-/- mast cells. Because apoptosis is abnormally reduced in bim-/- mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.
Animals↗
Mast cells enhance T cell activation: Importance of mast cell-derived TNF.
Mast cells are not only important effector cells in immediate hypersensitivity reactions and immune responses to pathogens but also can contribute to T cell-mediated disorders. However, the mechanisms by which mast cells might influence T cells in such settings are not fully understood. We find that mast cells can enhance proliferation and cytokine production in multiple T cell subsets. Mast cell-dependent enhancement of T cell activation can be promoted by FcepsilonRI-dependent mast cell activation, TNF production by both mast cells and T cells, and mast cell-T cell contact. However, at high concentrations of cells, mast cells can promote T cell activation independent of IgE or TNF. Finally, mast cells also can promote T cell activation by means of soluble factors. These findings identify multiple mechanisms by which mast cells can influence T cell proliferation and cytokine production.
Animals↗