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1.
Proteolytic maturation of insulin is a post-Golgi event which occurs in acidifying clathrin-coated secretory vesicles 总被引:48,自引:0,他引:48
The direct identification of the intracellular site where proinsulin is proteolytically processed into insulin has been achieved by immunocytochemistry using an insulin-specific monoclonal antibody. Insulin immunoreactivity is absent from the Golgi stack of pancreatic B-cells and first becomes detectable in clathrin-coated secretory vesicles released from the trans Golgi pole. Clathrin-coated secretory vesicles transform into mature noncoated secretory granules which contain the highest concentration of insulin immunoreactive sites. Maturation of clathrin-coated secretory vesicles is accompanied by a progressive acidification of the vesicular milieu, as evidenced by a cytochemical probe that accumulates in acidic compartments whereupon it can be revealed by immunocytochemistry. Thus packaging of the prohormone in secretory vesicles, and acidification of this compartment, are critical steps in the proper proteolytic maturation of insulin. 相似文献
2.
The addition of recombinant murine tumor necrosis factor alpha (rmTNF-alpha) to serum-free methylcellulose cultures inhibited macrophage colony formation stimulated by purified colony stimulating factor-1 (CSF-1), recombinant granulocyte-macrophage-CSF (rmGM-CSF), and recombinant interleukin 3 (rmIl-3). The concentration of rmTNF-alpha inhibiting colony formation by 50% (IC50) was between 2 and 20 ng/ml. Erythroid colony formation in cultures with erythropoietin (EPO) alone or EPO, rmIl-3, and rmGM-CSF in combination were reduced to a much lesser extent. In established long-term marrow cultures (LTMC), addition of 20 and 200 ng/ml of rmTNF-alpha resulted in release of cells from the adherent layer during the first week. Treatment of cultures with rmTNF-alpha for 4 consecutive weeks led to prolonged inhibition of cell production lasting up to 8 weeks after cessation of treatment. One day after addition of a low dose of TNF (2 ng/ml), "fat" cells were no longer observed in the adherent layer. Our results indicate that TNF inhibition of hemopoiesis occurs both at the progenitor cell and stromal cell levels. 相似文献
3.
Recombinant murine IL-3 fails to stimulate T or B lymphopoiesis in vivo, but enhances immune responses to T cell-dependent antigens 总被引:4,自引:0,他引:4
M Kimoto V Kindler M Higaki C Ody S Izui P Vassalli 《Journal of immunology (Baltimore, Md. : 1950)》1988,140(6):1889-1894
We have explored the in vivo effect of IL-3 on the lymphopoiesis and humoral responses of mice bearing osmotic minipumps loaded with murine rIL-3 for 1 to 4 wk. A marked splenomegaly due to the accumulation of hemopoietic precursors was seen, but no increase was found in the lymphoid organs in the total number of cells belonging to the T or B lymphocyte lineage, i.e., of L3T4+ or Lyt-2+, or of allospecific cytotoxic T lymphocyte precursor for the T lineage, or of sIg+ or B220+ cells, or of B colony-forming cells for the B lineage; total activity of natural killer and lymphokine-activated killer cells was decreased. In contrast to the splenomegaly, a marked diminution in the number of thymocytes was observed, suggesting that rIL-3 in large amounts does suppress the T lymphopoiesis, perhaps as the result of the selective stimulation of early progenitor cells toward the hemopoietic pathway. rIL-3 perfusion during immunization increased the IgM and IgG responses to a T cell-dependent antigen, human IgG, and prevented tolerance induction by the deaggregated human IgG, although in the same conditions it did not modify the response to a T cell-independent antigen. Our results suggest that in vivo IL-3 does not act directly on lymphocytes or their precursors, but may potentiate the humoral immune response to T cell-dependent antigens, presumably by acting on accessory cells. 相似文献
4.
We have used a stable clonal variant (D + Sc), isolated from the LLC-PK1 pig kidney-derived cell line and selected for its extensive capacity to form domes, in order to study the hormonal modulation of epithelial permeability in culture. Calcitonin, vasopressin, and other agents that raise intracellular adenosine 3',5'-cyclic monophosphate levels caused a rapid and dramatic decrease in the size and number of domes. This effect was independent of RNA and protein synthesis, and thus appeared unrelated to the production of urokinase, a proteinase synthesized by the cells in response to these agents. Calcitonin caused a decrease in transepithelial electrical resistance, suggesting that the effect of the hormone on domes was due to an increase in the permeability of a paracellular pathway. Thus, in addition to the wellknown effects of vasopressin on collecting duct permeability, part of the in vivo effect(s) of calcitonin and vasopressin on the renal tubule might also involve alterations of epithelial permeability related to those described here. 相似文献
5.
Characterization of cytoplasmically oriented Golgi proteins with a monoclonal antibody 总被引:8,自引:5,他引:3 下载免费PDF全文
BALB/c mice were repeatedly immunized with a galactosyl transferase- rich microsomal fraction of rat myeloma cells. Spleen cells were subsequently fused with Sp2/0 mouse myeloma cells, the resulting hybridomas were cloned, and their secreted Ig was screened for reactivity with antigens belonging to the Golgi complex. One such monoclonal antibody, 6F4C5, gave especially intense immunofluorescent staining of the Golgi area of myeloma cells and fibroblasts. It recognized two proteins bands on immunoblots of gel-fractionated cell lysates: a major one with an estimated Mr of 54,000 and a minor one at 86,000. Both proteins were concentrated in microsomal fractions isolated at low ionic strength. They were hydrophilic judging from partitioning of a Triton X-114 cell lysate. Both were cytoplasmically oriented as demonstrated by protease and high KCl treatments of postmitochondrial supernatants and microsomal fractions. Neither was retained by columns of insolubilized wheat germ agglutinin or concanavalin A, which suggests that they are not glycoproteins. Their more detailed location in the Golgi complex was studied by immunoelectron microscopy, using a saponin permeabilization procedure and peroxidase-conjugated reagents. The observed staining was restricted to two or three cisternae in the medial part of the stack. Nevertheless, differential centrifugation experiments indicated that the two antigens may be recovered in distinct subcellular fractions: this may be related to the unexpected observation that rather low salt concentrations strip the antigens from microsomal fraction. 相似文献
6.
Although the existence of an increasing number of angiogenesis-regulating cytokines is well documented, the response elicited by combinations of these cytokines is largely unknown. Using an in vitro model in which microvascular endothelial cells can be induced to form capillary-like tubes within three-dimensional collagen or fibrin gels, we have investigated the effect of transforming growth factor-β1 (TGF-β1) on basic fibroblast growth factor (bFGF)-induced and vascular endothelial growth factor (VEGF)-induced angiogenesis. Endothelial cell invasion and capillary lumen formation were inhibited by TGF-β1 at relatively high concentrations (5-10 ng/ml), while lower concentrations (100 pg/ml-1 ng/ml) of TGF-β1 potentiated the effect of bFGF- and VEGF-induced invasion. The optimal potentiating effect was observed at 200-500 pg/ml TGF-β1. At invasion-potentiating doses of TGF-beta;1, lumen size in fibrin gels was markedly reduced compared to that in cultures treated with bFGF alone. These results show that TGF-β1 exerts a biphasic effect on bFGF- and VEGF-induced angiogenesis in vitro. Our studies support the notion that the nature of the angiogenic response elicited by a specific cytokine is contextual, i.e., depends on the presence and concentration of other cytokines in the pericellular environment of the responding endothelial cell. 相似文献
7.
Protease-nexin I as an androgen-dependent secretory product of the murine seminal vesicle. 总被引:3,自引:0,他引:3 下载免费PDF全文
J D Vassalli J Huarte D Bosco A P Sappino N Sappino A Velardi A Wohlwend H Ern D Monard D Belin 《The EMBO journal》1993,12(5):1871-1878
A search for inhibitors of urokinase-type plasminogen activator (uPA) in the male and female murine genital tracts revealed high levels of a uPA ligand in the seminal vesicle. This ligand is functionally, biochemically and immunologically indistinguishable from protease-nexin I (PN-I), a serpin ligand of thrombin and uPA previously detected only in mesenchymal cells and astrocytes. A survey of murine tissues indicates that PN-I mRNA is most abundant in seminal vesicles, where it represents 0.2-0.4% of the mRNAs. PN-I is synthesized in the epithelium of the seminal vesicle, as determined by in situ hybridization, and is secreted in the lumen of the gland. PN-I levels are much lower in immature animals, and strongly decreased upon castration. Testosterone treatment of castrated males rapidly restores PN-I mRNA levels, indicating that PN-I gene expression is under androgen control. 相似文献
8.
Tumor promoter PMA stimulates the synthesis and secretion of mouse pro-urokinase in MSV-transformed 3T3 cells: this is mediated by an increase in urokinase mRNA content 总被引:12,自引:2,他引:10 下载免费PDF全文
In mouse MSV-3T3 cells the synthesis of the urokinase form of plasminogen activator was increased 10-fold after addition of the tumor promoter phorbol-12-myristate-13-acetate (PMA). PMA also stimulated the secretion of the protein into the culture medium, mostly in the form of enzymatically inactive pro-urokinase. When assayed by injecting RNA into Xenopus laevis oocytes, the concentration of functional urokinase mRNA was found to be 6- to 10-fold higher in the PMA-treated cells; a similar increase in urokinase mRNA content was measured by hybridisation with a mouse urokinase cDNA probe. Thus, the induction of plasminogen activator by PMA in MSV-3T3 cells is accounted for by an increased content of urokinase mRNA. 相似文献
9.
M S Pepper A P Sappino R Montesano L Orci J D Vassalli 《Journal of cellular physiology》1992,153(1):129-139
It has been proposed that a finely tuned protease-anti-protease equilibrium must be maintained during processes of cell migration in order to limit extracellular proteolysis to the close proximity of the cell surface, and thereby to prevent excessive extracellular matrix degradation. We have previously shown that urokinase-type plasminogen activator (u-PA) activity is induced in microvascular endothelial cells migrating from the edges of a wounded monolayer in vitro (Pepper et al., J. Cell Biol., 105:2535-2541, 1987). By Northern analysis, we now demonstrate that plasminogen activator inhibitor 1 (PAI-1) mRNA is increased in multiple-wounded monolayers of bovine microvascular (BME) or aortic (BAE) endothelial cells, with a maximal 7- and 9-fold increase 4 h after wounding, respectively. By in situ hybridization, we demonstrate that the increase in PAI-1 mRNA is localized to cells at the edge of a wounded BME or BAE cell monolayer. The increase in PAI-1 mRNA observed in BME cells is independent of cell division and is inhibited by antibodies to basic fibroblast growth factor (bFGF), suggesting that PAI-1 induction in migrating cells is mediated by the autocrine activity of bFGF. Taken together with our previous observations on the induction of u-PA, these results support the hypothesis that the proteolytic balance in the pericellular environment of migrating cells is regulated through the concomitant production of proteases and protease inhibitors. 相似文献
10.
Transient translational silencing by reversible mRNA deadenylation. 总被引:26,自引:0,他引:26
J Huarte A Stutz M L O'Connell P Gubler D Belin A L Darrow S Strickland J D Vassalli 《Cell》1992,69(6):1021-1030