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PubMedDate not supplied

Electron microscopical morphology of cytoplasmic granules from horse eosinophil leucocytes.

The structure of specific granules from horse eosinophil leukocytes is still largely unknown. In this work, electron microscopical studies of horse eosinophils reveal that the large cytoplasmic granules contain an external membrane, a matrix of less density, and a dense (non crystalline) core. Round vacuolar inclusions of matrix materials were often observed within the cores. Horse eosinophil granules showed a considerable heterogeneity, and three morphological types could be identified according to structural features of the core and matrix.

Animals↗
PubMed1995

Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells.

Cytokine-induced killer (CIK) cells are non-major histocompatibility complex-restricted cytotoxic cells generated by incubation of peripheral blood lymphocytes with anti-CD3 monoclonal antibody (MoAb), interleukin-2 (IL-2), IL-1, and interferon-gamma. Cells with the greatest effector function in CIK cultures coexpress CD3 and CD56 surface molecules. CIK cell cytotoxicity can be blocked by MoAbs directed against the cell surface protein leukocyte function associated antigen-1 but not by anti-CD3 MoAbs. CIK cells undergo release of cytoplasmic cytotoxic granule contents to the extracellular space upon stimulation with anti-CD3 MoAbs or susceptible target cells. Maximal granule release was observed from the CD3+ CD56+ subset of effector cells. The cytoplasmic granule contents are lytic to target cells. Treatment of the effector cells with a cell-permeable analog of cyclic adenosine monophosphate (cAMP) inhibited anti-CD3 MoAb and target cell-induced degranulation and cytotoxicity of CIK cells. The immunosuppressive drugs cyclosporin (CsA) and FK506 inhibited anti-CD3-mediated degranulation, but did not affect cytotoxicity of CIK cells against tumor target cells. In addition, degranulation induced by target cells was unaffected by CsA and FK506. Our results indicate that two mechanisms of cytoplasmic granule release are operative in the CD3+ CD56+ killer cells; however, cytotoxicity proceeds through a cAMP-sensitive, CsA- and FK506-insensitive pathway triggered by yet-to-be-identified target cell surface molecules.

Biomarkers↗
PubMed2001

Lobular carcinoma with cytoplasmic granules.

We report on a case of invasive lobular carcinoma of the breast with a previously undescribed cytologic feature. Diff-Quik-stained cytologic preparations showed uniform single cells with prominent coarse cytoplasmic granules. Ultrastructurally, the granules showed features suggestive of autophagosomes and/or degenerative mitochondria. The cytologic differential diagnosis included granulocytic sarcoma, metastatic melanoma, extramedullary hematopoiesis, large granulocytic leukemia/lymphoma, and mast-cell tumor. Adjunctive studies were helpful in the diagnosis of carcinoma. Histologic study of the mastectomy specimen showed classic type of invasive lobular carcinoma.

Aged↗
PubMed1993

Unique T-helper leukaemia with cytoplasmic granules and convoluted nuclei.

An unusual case of CD4+ helper T-cell lymphocytic leukaemia is reported in a 67-year-old Japanese woman. CD4+ cells showed convoluted nuclei and dense cytoplasmic granules, features usually present in CD8+ large granular lymphocytes and disorders of this particular cell type. Serum did not show antibodies to HTLV-I and HTLV-I proviral DNA integration was not evident by Southern blot analysis or after PCR. A monoclonal rearrangement of the TCR-beta chain gene was evident when hybridization methods were used. The patient died 11 months after diagnosis. No skin involvement, or splenomegaly was evident. Serum LDH levels were markedly elevated but serum calcium levels were within normal limits. The case is discussed and compared to other T-cell lymphoid leukaemias. The heterogeneity in the morphology of CD4+ T cell leukaemias is stressed.

Aged↗
PubMed1997

Isolation and partial characterization of cytoplasmic granules of LAK cells from mice showing side effects of recombinant human IL-2.

The side effects of recombinant human interleukin-2 (rhIL-2) in mice are considered to be mediated by lymphokine-activated killer (LAK) cells that have cytoplasmic granules and infiltrate into target organs. In cloned cytotoxic lymphocytes (CLs) including LAK cells in vitro, granule exocytosis is one of the mechanisms in target cell lysis, and hemolytic and BLT-serine esterase (BLT-SE) activities detected in the granules are important to the cytotoxicity of the CLs in vitro. However, no information is available on these activities of LAK granules in vivo in mice showing the side effects of rhIL-2. Therefore, the present study was designed to isolate the LAK granules from the homogenate of LAK cell-rich subcutaneous tissue in mice treated with continuous infusion of a dose of rhIL-2 that induces known toxicity. High activities in hemolysis and BLT-SE were detected in Percoll fractions from the tissue homogenate. Electron microscopic observation of these fractions revealed almost only LAK granules. These results indicate that hemolytic and BLT-SE activities are detectable in the LAK granules in vivo, suggesting that the cells have potency for cytotoxicity via their granules and are involved in the toxicity of rhIL-2 in mice. In addition, perforin, which has been identified as a hemolytic protein in CL granules in vitro, was not detected by immunoblotting in the granule fraction of the LAK cells in vivo, indicating that the hemolytic activity of the LAK granules in vivo is not due to perforin.

Animals↗
PubMed1997

Human monocytes and neutrophils store transforming growth factor-alpha in a subpopulation of cytoplasmic granules.

Transforming growth factor-alpha (TGF-alpha) exerts several effects on target cells, such as neovascularization promotion and mitogenic signalling. Using immunoelectron microscopy, we show that monocytes and neutrophils, store TGF-alpha in cytoplasmic granules. In monocytes, TGF-alpha did not colocalize with components of peroxidase-positive granules or with albumin of secretory vesicles. Furthermore, no colocalization of TGF-alpha with components of azurophilic or specific granules or secretory vesicles was observed in neutrophils. Activated monocytes and tissue-macrophages contained much less TGF-alpha-positive granules, suggesting TGF-alpha release. Western blot analysis showed a protein of 10 kD in lysates of monocytes. TGF-alpha mRNA was detected in monocytoid cells from the bone marrow by in situ hybridization. This study shows for the first time that monocytes and neutrophils contain TGF-alpha in all stages of maturation and that TGF-alpha in monocytes is stored in a large population of peroxidase-negative granules suggesting a function for these granules. Monocytes and neutrophils are important effector cells in inflammatory reactions. The present finding that these cells contain TGF-alpha might explain complications such as fibrosis and neoplastic transformation, caused by chronic inflammation.

Bone Marrow↗
PubMed1986

Cytolytic and biochemical properties of cytoplasmic granules of murine lymphokine-activated killer cells.

The incubation of murine spleen cells in the lymphokine interleukin 2 (IL 2) gives rise to lymphokine-activated killer (LAK) cells capable of lysing fresh tumor cells in short-term lytic assays. During the course of cultures used to generate LAK cells, cytoplasmic granules were prepared and were analyzed for the presence of the cytolysin previously described in large granular lymphocytes (LGL) and cytotoxic T lymphocytes (CTL). Such cytolysin activity is initially undetectable, appears after 2 days of culture, and continues to increase until day 7. The LAK cytolysin has properties similar to those of previously described cytolysins with respect to nonspecific killing of various target cells, rapid kinetics, and absolute dependence on calcium. Antibodies raised against purified LGL tumor granules neutralized the activity of the LAK cytolysin. The precursors of both the LAK cells and the cells bearing the cytolysin are eliminated by treatment with anti-asialo-GM1 and complement, strongly suggesting that the actual LAK effector cells and the cytolysin-bearing cells are identical. Biochemical analysis of the LAK granules indicate that they contain the lysosomal enzyme arylsulfatase. The protein content of granules isolated from various days of culture with r-IL 2 undergoes a dramatic change, with major protein bands around 30,000 daltons becoming prominent, as well as the cytolysin protein band at 70,000 daltons. These data suggest that the mechanism of cell lysis by LAK cells is similar to that of CTL and natural killer-mediated lysis, and each of these forms of lymphocyte-mediated cytolysis is based on a granule exocytosis mechanism.

Animals↗
PubMed1989

Interactions of cytoplasmic granules with microtubules in human neutrophils.

Ultrastructural and functional studies of degranulation responses by human neutrophils have suggested that microtubules (MTs) have a role in the intracellular transport of neutrophil granules. We have found that granule-MT complexes can be isolated from disrupted taxol-treated (1.0 microM) neutrophils, visualized by electron microscopy, and quantified in terms of granules per MT length. After incubation of neutrophils with the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP), granule-MT complex formation was found to be increased two- to threefold. Enhanced binding of granules to MTs was detectable within 30 s of fMLP stimulation and was dependent on the concentration of fMLP. Incubation of cells with dibutyryl cAMP inhibited this fMLP-stimulated granule-MT complex formation in a dose-responsive fashion. These granule-MT interactions could be reproduced in a cell-free system with neutrophil granules isolated by density gradient centrifugation and MTs polymerized from phosphocellulose-purified tubulin. Furthermore, reconstituted granule-MT interactions were found to be modulated by ATPase inhibitors. Sodium orthovanadate increased granule-MT interactions in a concentration-dependent manner, while AMP-PNP, a nonhydrolyzable ATP analogue, and N-ethylmaleimide decreased or eliminated these interactions. In addition, we found that a MT-activated ATPase could be recovered from intact neutrophil granules by salt extraction, and that extracts enriched in this ATPase contained a polypeptide of between 115 and 120 kD which binds ATP and is immunologically related to kinesin. These studies demonstrate that cytoplasmic granules interact with MTs in human neutrophils in a regulated stimulus-responsive manner, and they suggest that such interactions may involve an MT-based, ATPase-dependent, vesicle translocation system as has been demonstrated in other types of cells.

Adenosine Triphosphatases↗
PubMed1999

Ribonuclease-gold labels proteoglycan-containing cytoplasmic granules and ribonucleic acid-containing organelles--a survey.

An enzyme-affinity-gold method to detect RNA in routinely prepared ultrastructural samples is based on the affinity of the gold-coupled enzyme, ribonuclease, for its substrate, RNA. High concentrations of a known inhibitor of RNase, heparin, are uniquely located in human mast cell granules. Specific labeling for the presence of heparin in these structures was determined using the RNase-gold (R-G) reagent based on the RNase inhibitor property of heparin. This property was used to probe for the presence of proteoglycans (PG) known to be present in a wide variety of ultrastructural samples, none of which contain heparin. In addition to known subcellular sites of RNA, the R-G reagent was shown to bind to PG-rich cytoplasmic granules in a wide variety of leukocytes and secretory cells of epithelial, endocrine, and neuroendocrine origin. This newly recognized property was used to image the changing distribution of labeled PGs during cellular maturation, secretion, and recovery from secretion of secretory cells in vivo, ex vivo, in vitro and in isolated, biochemically defined guinea pig basophil granule preparations.

Animals↗
PubMed1994

Annexin 3 is associated with cytoplasmic granules in neutrophils and monocytes and translocates to the plasma membrane in activated cells.

Annexins are soluble proteins capable of binding to phospholipid membranes in a calcium-dependent manner. Annexin 3, a 33 kDa protein mainly expressed in neutrophils, aggregates granules in cell-free assays, and a 36 kDa variant of this protein, specifically expressed in monocytes, has recently been identified. To obtain further information on these proteins, we defined their subcellular localization in resting and activated cells by immunofluorescence microscopy. Both proteins were associated with cytoplasmic granules in resting cells. We obtained evidence to indicate that, in neutrophils which possess a heterogenous granule population, annexin 3 was more likely to be associated with the specific granules. In cells activated with phorbol 12-myristate 13-acetate or opsonized zymosan, the 33 kDa and 36 kDa proteins translocated to the plasma or the phagosome membrane. Upon stimulation with A23187, annexin 3 translocated to the plasma membrane only in neutrophils. We also report that while annexin 3 was associated with restricted membranes in intact cells, it binds indiscriminately to every membrane fraction in cell-free assay. In conclusion, association of both forms of annexin 3 with granules suggests that these proteins could be implicated in processes of granule fusion.

Annexin A3↗
PubMed2001

Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms.

Tryptases are serine proteases primarily expressed in mast cells. Normal blood basophils express only trace amounts of the enzyme. However, recent immunohistochemical studies have raised the possibility that neoplastic basophils express significant amounts of tryptase. In this study, tryptase expression was analyzed in normal and neoplastic basophils by immunoelectron microscopy using antitryptase monoclonal antibody G3. Basophils were obtained from patients with chronic myeloid leukemia (CML), idiopathic myelofibrosis (IMF), and myelodysplastic syndrome (MDS), and from healthy donors. Tryptase-immunoreactive material was detected in cytoplasmic granules of basophils in CML, IMF, and MDS. By contrast, normal basophils did not contain significant amounts of tryptase by immunoelectron microscopy. As assessed by reverse transcription-polymerase chain reaction, neoplastic basophils contained messenger RNA (mRNA) for alpha-tryptase, but no beta-tryptase mRNA. In summary, these data provide evidence that neoplastic basophils in CML, IMF, and MDS can express detectable amounts of tryptase. Therefore, tryptase should not be regarded as specific for mast cells when neoplastic myeloid cells are analyzed.

Basophils↗
PubMed1984

Impaired natural killer activity in patients with chronic lymphocytic leukemia is associated with a deficiency of azurophilic cytoplasmic granules in putative NK cells.

This study was undertaken to gain further insight into the severely impaired natural killer (NK) activity we and others have previously observed in patients with chronic lymphocytic leukemia (CLL). Normal individuals' NK cells are large granular lymphocytes (LGL) that (A) bind to and lyse NK-sensitive cells, including K562, (B) express receptors for the Fc portion of IgG (FcR+ cells), and (C) express cell surface antigens reactive with monoclonal antibodies OKM1, 9.6, and OKT11A. We thus examined lymphocytes depleted of monocytes and B cells, from 6 CLL patients and 6 normal individuals, that were identified on the basis of binding to K562, expressing OKM1, or expressing receptors for the Fc portion of IgG. In the CLL patients studied, lymphocytes that bind to K562 cells, as well as OKM1+ cells isolated by fluorescence activated cell sorting, were morphologically similar to LGL of normal individuals, with the exception that more than 75% of the patients' cells were deficient in azurophilic cytoplasmic granules, which typify normal individuals' LGL. Furthermore, although the percentages of the patients' FcR+ cells reactive with OKT11A, 9.6 and OKM1 were very similar to those of normals, the majority of the patients' FcR+ cells were deficient in azurophilic granules and lacked NK activity. These findings indicate that the impaired NK activity in CLL patients is associated with cells that are phenotypically and morphologically NK cells, but which lack azurophilic granules that are thought to play a role in NK-mediated lysis.

Antibodies, Monoclonal↗
PubMed2003

Increased expression and localization of the RNA-binding protein HuD and GAP-43 mRNA to cytoplasmic granules in DRG neurons during nerve regeneration.

The neuronal-specific RNA-binding protein, HuD, binds to a U-rich regulatory element of the 3' untranslated region (3' UTR) of the GAP-43 mRNA and delays the onset of its degradation. We have recently shown that overexpression of HuD in embryonic rat cortical cells accelerated the time course of normal neurite outgrowth and resulted in a twofold increase in GAP-43 mRNA levels. Given this evidence, we sought to investigate the involvement of HuD during nerve regeneration. It is known that HuD protein and GAP-43 mRNA are expressed in the dorsal root ganglia (DRG) of adult rat and that GAP-43 is upregulated in DRG neurons during regeneration. In this study, we examined the expression patterns and levels of HuD and GAP-43 mRNA in DRG neurons following sciatic nerve injury using a combination of in situ hybridization, immunocytochemistry, and quantitative RT-PCR. GAP-43 and HuD expression increased in the ipsilateral DRG during the first 3 weeks of regeneration, with peak values seen at 7 days postcrush. At this time point, the levels of HuD and GAP-43 mRNAs in the ipsilateral DRG increased by twofold and sixfold, respectively, relative to the contralateral DRG. Not only were the temporal patterns of expression of HuD protein and GAP-43 mRNA similar, but also they were found to colocalize in the cytoplasm of DRG neurons. Moreover, both molecules were distributed in cytoplasmic granules containing ribosomal RNA. In conclusion, our results suggest that HuD is involved in the upregulation of GAP-43 expression observed at early stages of peripheral nerve regeneration.

Animals↗
PubMed2001

Secretory granule-cytoplasm relationships in serous glands of anurans: ultrastructural evidence and possible functional role.

A survey covering the serous (granular) cutaneous glands in several anuran families from the Old and New Worlds (Bombinatoridae, Discoglossidae, Ranidae, Hylidae, Pseudidae and Leptodactylidae) has revealed consistent patterns of complex interactions between the syncytial secretory unit and serous deposits (granules). These relationships involve outgrowths from the syncytial cytoplasm encircling the granules and complex invaginations of the perigranular compartment (halo) into the syncytium. The outgrowths are branched, cytoplasm processes resembling ramified microvilli, or can be larger, dome-like to cylindrical structures. Despite their different features and origins, all these structures are efficient devices for amplifying the cytoplasmic surfaces round the granules, so improving exchange between the secretory syncytium and serous product. These complex secretory granule-cytoplasm interactions affect the product released from the Golgi apparatus and are consistent with the hypothesis of prolonged serous maturation following the initial phase of biosynthesis. Post-Golgian maturation modifies the secretory material on a centripetal gradient, causing condensation and, possibly, the transfer of component molecules from and/or to the cytoplasm.

Animals↗