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PubMed1978

Regulation of the secretory process of granular components from the convoluted tubular cells of the mouse submandibular gland.

Autonomic regulation of the secretion of granule components in the convoluted tubular cells of male mouse submandibular glands was investigated with the use of an agar gel diffusion test using an antisera for male specific components. Whereas the injection of neither a parasympathomimetic agent (pilocarpine) nor a beta-adrenergic agent (isoproterenol) decreased the amount of the components in the glands, the injection of alpha-adrenergic agents (norepinephrine or phenylephrine) significantly decreased the amount of male specific components. Phenoxybenzamine, an alpha-blocker, completely inhibited these actions of norepinephrine and phenylephrine. These facts suggest that the alpha-adrenergic receptor participates in the secretion of male specific components present in the granules in the convoluted tubular cells of mouse submandibular glands.

Animals↗
PubMed1995

Glucagon-like peptide-1 affects gene transcription and messenger ribonucleic acid stability of components of the insulin secretory system in RIN 1046-38 cells.

It has been previously demonstrated that the enteric hormone glucagon-like peptide-1 (7-36 amide) (GLP-1) has acute effects on glucose-induced insulin secretion by RIN 1046-38 cells. In this study, we investigated the effects of extended exposure of RIN 1046-38 cells to GLP-1 and examine the mechanism by which GLP-1 synergizes with glucose in stimulating insulin secretion. Compared with cells cultured with glucose alone, incubation of cells with glucose plus 1 or 10 nM GLP-1 for 12 or 24 h significantly increased insulin release by about 3-fold, intracellular insulin content by 1.5-fold, and insulin messenger RNA (mRNA) by almost 2.5-fold. The insulinotropic effects of GLP-1 on RIN 1046-38 cells were accompanied by an up-regulation of both glucose transporter-1 (GLUT-1) and hexokinase I mRNA by about 2-fold. mRNA levels of GLUT-2 and glucokinase, which were low in controls, were unchanged by GLP-1 treatment. Treatment of cells with a transcription inhibitor, actinomycin D, demonstrated that elevated insulin mRNA levels after a GLP-1 exposure are mainly due to stabilization of the mRNA. In contrast, the elevated mRNA levels of GLUT-1 and hexokinase I are the result of increased transcription stimulated by GLP-1 exposure. Actinomycin D blunted the GLP-1 effect on insulin release but did not affect GLP-1 mediated elevation of insulin mRNA. This suggests that actinomycin D inhibits the transcription of the proteins necessary for insulin biosynthesis and insulin release, such as GLUT-1 and hexokinase I. Our study suggests that the mechanisms by which extended exposure of RIN 1046-38 cells to GLP-1 increases glucose-stimulated insulin secretion include significant up-regulation of glucose-sensing elements.

Animals↗
PubMed1999

Molecular and functional characterization of pituitary adenylate cyclase-activating polypeptide (PACAP-38)/vasoactive intestinal polypeptide receptors in pancreatic beta-cells and effects of PACAP-38 on components of the insulin secretory system.

It has been previously demonstrated that pituitary adenylate cyclase-activating polypeptide (PACAP) regulates insulin secretion. PACAP exerts its biological action by binding to at least three different receptor subtypes coupled to different signal transduction mechanisms. The signaling pathways underlying the insulinotropic effect of PACAP involve mainly the activation of adenylate cyclase to form cAMP, which directly and indirectly, through increased intracellular Ca2+, stimulates insulin exocytosis. In the present study we have characterized the functional and molecular expression of PACAP/vasoactive intestinal polypeptide receptors isoforms and subtypes and its isoforms in a beta-cell line and in isolated rat pancreatic islets. Although insulinoma cells express the messenger RNA encoding PAC1 (-R and -hop variants), VPAC1 and VPAC2, binding experiments indicate the preponderance of PAC1 over VPAC 1-2 receptors. We have also shown that the main signaling pathway of PACAP in beta-cells is mediated by adenylate cyclase, whereas the inositol 1,4,5-trisphosphate pathway is almost inactive. Furthermore, we have demonstrated that PACAP exerts long-term effects on beta-cells, such as transcriptional regulation of the insulin gene and genes of the glucose-sensing system (GLUT1 and hexokinase 1).

Adenylyl Cyclases↗
PubMed2004

Recycling of the dense-core vesicle membrane protein phogrin in Min6 beta-cells.

Phogrin (IA2-beta) is an integral membrane protein of dense-core vesicles in neuroendocrine cells. We have examined the recycling of endogenous phogrin following exocytosis in insulin secreting Min6 beta-cells by monitoring stimulus dependent-uptake of antibodies directed against the lumenal domain of the protein. While low levels of internalized phogrin accumulated in LAMP1-positive lysosomes, more than 35% of internalized phogrin recycled back to an insulin-positive compartment and could return to the cell surface during a second exocytic stimulation. The recycling phogrin transited a syntaxin 6-positive compartment but did not appear to go through the TGN38-positive trans Golgi network. The results suggest a model in which secretory membrane components can recycle from the endosomal system to immature secretory granules without interaction with the major portion of the TGN.

Animals↗
PubMed1995

A functional cyclic AMP response element plays a crucial role in neuroendocrine cell type-specific expression of the secretory granule protein chromogranin A.

Chromogranin A, a soluble acidic protein, is a ubiquitous component of secretory vesicles throughout the neuroendocrine system. We reported previously the cloning and initial characterization of the mouse chromogranin A gene promoter, which showed that the promoter contains both positive and negative domains and that a proximal promoter spanning nucleotides -147 to +42 bp relative to the transcriptional start site is sufficient for neuroendocrine cell type-specific expression. The current study was undertaken to identify the particular elements within this proximal promoter that control tissue-specific expression. We found that deletion or point mutations in the potential cAMP response element (CRE) site at -68 bp virtually abolished promoter activity specifically in neuroendocrine (PC12 chromaffin or AtT20 corticotrope) cells, with little effect on activity in control (NIH3T3 fibroblast) cells; thus, the CRE box is necessary for neuroendocrine cell type-specific activity of the chromogranin A promoter. Furthermore, the effect of the CRE site is enhanced in the context of intact (wild-type) promoter sequences between -147 and -100 bp. DNase I footprint analysis showed that these regions (including the CRE box) bind nuclear proteins present in both neuroendocrine (AtT20) and control (NIH3T3) cells. In AtT20 cells, electrophoretic mobility shift assays and factor-specific antibody supershifts showed that an oligonucleotide containing the chromogranin A CRE site formed a single, homogeneous protein-DNA complex containing the CRE-binding protein CREB. However, in control NIH3T3 cells we found evidence for an additional immunologically unrelated protein in this complex. A single copy of this oligonucleotide was able to confer neuroendocrine-specific expression to a heterologous (thymidine kinase) promoter, albeit with less fold selectivity than the full proximal chromogranin A promoter. Hence, the CRE site was partially sufficient to explain the neuroendocrine cell type specificity of the promoter. The functional activity of the CRE site was confirmed through studies of the endogenous chromogranin A gene. Northern mRNA analysis showed that expression of the endogenous chromogranin A gene was stimulated seven- to eightfold by cAMP in PC12 cells, whereas no induction occurred in the NIH3T3 cells. Similar cAMP induction was obtained with the transfected chromogranin A promoter in PC12 cells, and abolition of the CRE site (by deletion or point mutation) eliminated the induction. Thus, the CRE site in the chromogranin A proximal promoter is functional and plays a crucial, indeed indispensable, role in neuroendocrine-specific expression of the gene. These results also provide insight into transcriptional mechanisms governing acquisition of the neuroendocrine secretory phenotype.

3T3 Cells↗
PubMed2001

Immunoprotection of gonads and genital tracts in human embryos and fetuses: immunohistochemical study.

PROBLEM: The immune protection of genital organs in embryogenesis has not been sufficiently studied. The purpose of this study was to investigate the development of the secretory immune system (SIS) in the gonads and genital tracts of human embryos and fetuses. MATERIALS AND METHODS: Developing gonads at different stages and genital tracts from 18 embryos and 39 fetuses in the first to third trimester of gestation were analyzed for presence of different component of SIS: secretory component (SC), joining (J) chain. IgA, IgM, IgG, macrophages, and subsets of lymphocytes. The material was divided into two groups: cases not subjected to foreign antigenic effects (group I, n = 31) and those under antigenic attack (chorioamnionitis, group II, n = 26). RESULTS: In embryos and fetuses of group I, SC, J chain, and IgG were seen in the epithelium of mesonephric and paramesonephric ducts, proliferating coelomic epithelium, epithelium of the uterine tubes and uterus, epithelium of the vas deferens, epididymis, and rete testis. IgA and IgM appeared in 6-week-old embryos. J chain, IgA, IgM, and IgG, but not SC, were found in the primary oocytes and oogonia, spermatogonia. and interstitial cells. An abundance of macrophages was seen in 4-week-old embryos. T and B lymphocytes first appeared in 6-7-week-old embryos. In embryos and fetuses of group II, reactivity of immunoglobulins (Igs) decreased until they disappeared altogether. CONCLUSIONS: Components of SIS were seen in genital organs in 4-5-week-old embryos and were present during the whole intrauterine period. We suggest the presence of two forms of immune protection of fetal genital organs. One form contains SC, J chain, and Igs and is present in the genital tract epithelium. The second form contains only J chain and Igs and is present in germ cells of gonads. The loss of Igs in cases with chorioamnionitis reflects the functional participation of the SIS of genital organs in response to antigen attack.

Antigens, CD↗
PubMed1992

Airway epithelial cell mucin release: immunologic quantitation and response to platelet-activating factor.

Mucus production is an integral component of airway mucosal inflammation. Platelet-activating factor (PAF) is a phospholipid mediator implicated in the pathogenesis of many inflammatory processes, including airway inflammation. PAF functions as a mucus secretagogue when mucus is quantitated as radiolabeled glycoconjugates released from airway organ cultures. To more directly assess the interaction of PAF and airway epithelial mucous cell secretion, we used primary feline tracheal epithelial cell cultures and an immunoassay for a specific mucous cell secretory vesicle component. Cultured tracheal epithelial cells were shown to synthesize and secrete glycoconjugates with mucin characteristics. These mucin-type glycoconjugates were immunoreactive with a mucous cell-specific antibody. Localization of this antibody to components of the secretory vesicles of cultured epithelial cells was confirmed by electron microscopic immunogold labeling. Using this monoclonal antibody, an immunoassay was developed to quantitate release of immunoreactive material into cell culture media. Exposure of cultures to PAF produced a concentration-dependent, prompt release of immunoreactive material. Concentration-dependent inhibition of this effect was demonstrated by coincubation with the PAF receptor antagonists, WEB 2086 and Ro 19-3704. A component of the signal transduction pathway for PAF effects was studied in cultured tracheal epithelial cells by coincubation of PAF with nordihydroguaiaretic acid (NDGA), a combined lipoxygenase and cyclooxygenase inhibitor, or p-bromophenacyl bromide (BPB), an inhibitor of cellular arachidonic acid release. Both NDGA and BPB blocked PAF-stimulated mucin release in a concentration-dependent manner. These studies demonstrate a direct airway epithelial mucous cell secretagogue effect that appears to be dependent upon airway epithelial PAF receptors and altered cellular lipid metabolism. These findings suggest a direct and potent mechanism for goblet cell secretion during airway inflammation.

Animals↗
PubMed1987

Electron microscopic studies of Moll's gland cyst.

Several Moll's gland cysts from 4 different patients were studied with the light and electron microscopes. The cysts were lined with a combination of several different epithelia, such as completely keratinized epithelium, glycogen-rich, stratified squamous epithelium with incompletely keratinized luminal cells, sweat duct epithelium, and secretory cells. In one case in addition to the above components, secretory-type wall cells contained very large lamellar inclusions which were PAS positive and diastase resistant. It was concluded that Moll's gland cyst is composed of dilated duct of the Moll's gland and secretory segment; the proportion of each segment is variable but the portion showing ductal differentiation is usually predominant and typical secretory epithelium is not always seen.

Aged↗
PubMed1997

Mucosal immunity in the urinary tract: changes in sIgA, FSC and total IgA with age and in urinary tract infection.

The incidence of primary urinary tract infection (UTI) is greatest in the first month of life and decreases with age throughout childhood. Secretory immunoglobulin A (sIgA) is an important component of mucosal immunity. The changes in secretory IgA, IgA and free secretory component (FSC) during the first year of life were examined in relation to age, sex and in infants, feeding practice. These constituents were further compared between healthy children and those with acute and recurrent UTI. Urine was collected from 41 healthy infants (16 female: 25 male) at intervals (mean age 1.4, 9.1, 44, 91, 210 and 412 days), 139 healthy children (75 female: 64 male), 29 children with histories of recurrent UTI (25 female: 4 male) and 10 with acute UTI (8 female: 2 male). sIgA, IgA and FSC were measured by enzyme linked immunoassay. In the majority of children sIgA and IgA were undetectable at birth. SIgA and IgA rose significantly during the first year then levelled off throughout childhood. FSC was detectable from birth (geometric mean [mean of logged values]-GOM at day 1.4, 362.2 ng/ml). No sex differences were apparent for any of the three constituents at any age. Breast feeding was associated with higher levels of sIgA and IgA than bottle feeding. This was highly significant at 9.1 days when sIgA and IgA levels of breast fed compared with bottle fed infants were 64.6 ng/ml vs 21.2 and 56.2 ng/ml vs 18.7 ng/ml respectively, giving a GOM ratio of 3.04 for sIgA and 3.0 for IgA (p < 0.001 for both). No significant difference in the three parameters were demonstrable when children with recurrent UTI-with normal or abnormal renal tracts-were compared with controls. Acute UTI resulted in raised sIgA, IgA and FSC compared with controls (GOM ratio of 4.9 [p < 0.002], 4.2 [p < 0.005] and 2.7 [p < 0.001] respectively). The proportion of total IgA present as sIgA (sIgA/total IgA) was not significantly different in the acute vs control groups. Urinary sIgA and IgA may be important for the observed variation with age in infant UTI and the reduced incidence in breast fed infants but does not appear to contribute to the sex associated difference in susceptibility to infection at any age.

Acute Disease↗
PubMed2004

XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation.

The differentiation of B cells into immunoglobulin-secreting plasma cells is controlled by two transcription factors, Blimp-1 and XBP1. By gene expression profiling, we defined a set of genes whose induction during mouse plasmacytic differentiation is dependent on Blimp-1 and/or XBP1. Blimp-1-deficient B cells failed to upregulate most plasma cell-specific genes, including xbp1. Differentiating xbp1-deficient B cells induced Blimp-1 normally but failed to upregulate genes encoding many secretory pathway components. Conversely, ectopic expression of XBP1 induced a wide spectrum of secretory pathway genes and physically expanded the endoplasmic reticulum. In addition, XBP1 increased cell size, lysosome content, mitochondrial mass and function, ribosome numbers, and total protein synthesis. Thus, XBP1 coordinates diverse changes in cellular structure and function resulting in the characteristic phenotype of professional secretory cells.

Animals↗
PubMed2001

Purification and characterization of a major secretory cellobiase, Cba2, from Cellulomonas biazotea.

A novel cellobiase (Cba2) was purified from the culture supernatant of Cellulomonas biazotea and characterized. Cba2 appeared to be a major secretory cellobiase in C. biazotea as its enzymatic activity was estimated to represent over 40% of the total extracellular beta-glucosidase activity. The enzyme was purified over 260-fold subsequent to ammonium sulfate precipitation, gel-filtration chromatography, anion-exchange chromatography, and reversed-phase high-performance liquid chromatography. Cba2 was shown by SDS-PAGE to have a large molecular mass of 109 kDa, which makes it one of the largest secretory cellobiases characterized. Its homogeneity was confirmed by N-terminal amino acid sequencing. The K(m) and V(max) values were 0.025 mM and 0.0048 mM min(-1), respectively, for the Cba2 hydrolysis of p-nitrophenyl-beta-d-glucopyranoside, and 0.73 mM and 0.00033 mM min(-1), respectively, for the hydrolysis of cellobiose (at 37 degrees C and pH 7.0). The purified enzyme has a pH optimum of 4.8 and the optimum temperature for activity is 70 degrees C. In view of the secretory nature of Cba2 and the fact that it is a major component of secretory cellobiases of C. biazotea, it is potentially important in the enzymatic degradation of cellulose, and its availability as a recombinant protein may facilitate the studies of its biotechnological applications.

Actinomycetales↗
PubMed2002

The novel serpin endopin 2 demonstrates cross-class inhibition of papain and elastase: localization of endopin 2 to regulated secretory vesicles of neuroendocrine chromaffin cells.

This study demonstrates that endopin 2 is a unique secretory vesicle serpin that displays cross-class inhibition of cysteine and serine proteases, indicated by effective inhibition of papain and elastase, respectively. Homology of the reactive site loop (RSL) domain of endopin 2, notably at P1-P1' residues, with other serpins that inhibit cysteine and serine proteases predicted that endopin 2 may inhibit similar proteases. Recombinant N-His-tagged endopin 2 inhibited papain and elastase with second-order rate constants (k(ass)) of 1.4 x 10(6) and 1.7 x 10(5) M(-1) s(-1), respectively. Endopin 2 formed SDS-stable complexes with papain and elastase, a characteristic property of serpins. Interactions of the RSL domain of endopin 2 with papain and elastase were indicated by cleavage of endopin 2 near the predicted P1-P1' residues by these proteases. Endopin 2 did not inhibit the cysteine protease cathepsin B, or the serine proteases chymotrypsin, trypsin, plasmin, and furin. Endopin 2 in neuroendocrine chromaffin cells was colocalized with the secretory vesicle component (Met)enkephalin by confocal immunonfluorescence microscopy, and was present in isolated secretory vesicles (chromaffin granules) from chromaffin cells as a glycoprotein of 72-73 kDa. Moreover, regulated secretion of endopin 2 from chromaffin cells was induced by nicotine and KCl depolarization. Overall, these results demonstrate that the serpin endopin 2 possesses dual specificity for inhibiting both papain-like cysteine and elastase-like serine proteases. These findings demonstrate that endopin 2 inhibitory functions may occur in the regulated secretory pathway.

Amino Acid Sequence↗
PubMedDate not supplied

Secretory immune response in patients with oropharyngeal carcinoma.

The secretory immune system is a unique, local immunological mechanism which appears to be independent of systemic immunity. Secretory immunoglobulin A (SIgA), a major component in this mucosal immune system, is structurally different from the IgA immunoglobulin in serum and has a function as a first line of defense against the uptake of macromolecules and against infectious agents in the intestine, respiratory tract and genitourinary system. However, its relationship to the development and control of neoplasia is not well understood despite the fact that the major portion of human malignancies are of the epithelial type and located where the secretory immune system is vigorously functioning. In this study, the amounts of SIgA and secretory component (SC) in oral secretions and sera were measured in 20 patients with oropharyngeal carcinoma and 22 appropriate control subjects in order to elucidate the involvement of the secretory immune system as it related to oropharyngeal carcinoma. Cancer patients had increased IgA levels in oral secretions (561 +/- 161 micrograms/ml) compared to normal subjects (166 +/- 18 micrograms/ml, p less than 0.02) and to a smoker/drinker subgroup of controls (229 +/- 8.7 micrograms/ml, p less than 0.05). The elevated IgA levels in cancer patients appear to be unrelated to local inflammation or the patient's history of smoking or drinking. Density gradient analysis demonstrated that the IgA measured in oral secretions migrates at the 11S position, confirming that it is of the secretory type and indicating that the increased levels of IgA in oral secretions of patients with oropharyngeal carcinoma are not due to nonspecific leakage of 7 SIgA from sera. Secretory component levels in sera also revealed highly significant differences between cancer patients (1.65 +/- 0.73 micrograms/ml) and all control subjects (0.85 +/- 0.12 micrograms/ml, p less than 0.002). The data suggest that the increased SIgA concentration in secretions and SC level in sera accompany the existence of oropharyngeal carcinoma. The biological significance of these findings and their possible clinical application are discussed.

Adult↗
PubMed1994

Macrophage activation: a riddle of immunological resistance.

Various lines of defense against infection are present in all living creatures. The balance between symbiosis and parasitism is determined by the mechanisms through which the host resists infection and by the extent of injury induced by the parasite: both factors contribute to disease. Lines of host defense can be arbitrarily divided into three components: 1) barrier functions of skin and mucous membranes and their innate physical and secretory antimicrobial components; 2) elements of host defense that do not necessarily require prior exposure to an infectious agent or immunologic memory (mast cells, granulocytes, macrophages, NK cells, gamma/delta T cells); and 3) immune responses directed against specific epitopes on the infectious agent induced by prior exposure and immunologic memory (alpha/beta T cells, B cells). Analysis of such host defense mechanisms repeatedly documents tremendous redundancy and overlap between these lines of defense. Further, there is open communication, so that a change at any one level ripples throughout the system. Acquired nonspecific resistance to infection is an example of such a ripple. Host response to one infection alerts the immune system, so that the general level of resistance to other infectious agents is increased. This response is initiated by an immune response (third line of defense) but effected by nonspecific elements (second line of defense). The survival value of such responses is obvious. There are numerous examples in both mouse and man of the operation of these systems in response to infection. Further, the menus of antimicrobial components available to both mouse and man for resistance to infection are very similar, but not identical. Indeed, it is said that the genetic basis for differences between mice and man revolve around a difference of less than 10% in DNA sequences. But there are differences! Mouse macrophages produce IFN-beta in response to infection, human cells produce IFN-alpha. Mouse macrophages effect antimicrobial activity principally through induction of NO synthase and the generation of toxic nitrogen oxides. This pathway has yet to be described with human macrophages. In both man and mouse, F. tularensis is an obligate intracellular parasite of macrophages that requires an essential component provided by the cell for its replication. That mouse and man are not so different is well illustrated by the effector mechanisms induced by IFN-gamma for antimicrobial activity against F. tularensis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗