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PubMed1994

Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype.

Immunocompetent T lymphocytes in peripheral tissues mainly secrete IL-2 when first stimulated, whereas effector T lymphocytes generated during an immune response secrete different cytokine patterns, such as the Th1, Th2, or other phenotypes displayed by in vitro T cell clones. In this paper, we have examined whether the cell populations that have distinctive cytokine-producing capabilities represent different cell lineages or whether they are derived from the same uncommitted precursor T cell. During allostimulation of CD4+ spleen T cells, TGF-beta inhibited the development of T cells that could produce the Th2 cytokines IL-4 and IL-5. Anti-IFN-gamma inhibited the development of Th1-like IFN-gamma-secreting cells, and the combination of TGF-beta and anti-IFN-gamma resulted in the proliferation of a cell population that produced IL-2, but not IFN-gamma, IL-4, or IL-5, on restimulation. These IL-2-producing T cells expressed low levels of CD45RB and MEL14 and high levels of CD44. Clones of IL-2-producing T cells were isolated, and either bulk culture or clonal IL-2-producing populations acquired the ability to secrete Th1 or Th2 cytokine patterns when restimulated in the presence of TGF-beta or IL-4, respectively. These results demonstrate that both Th1- and Th2-like cells can be derived from a bipotential IL-2-producing precursor CD4+ T cell.

Animals↗

PubMed1993

Duplication of secretion signal sequences is deleterious for the secretion of human interferon alpha 4 from Saccharomyces cerevisiae and Bacillus subtilis.

Tandem duplication of a mitochondrial import leader sequence has been shown to markedly increase the efficiency of translocation of chimaeric precursors across mitochondrial membranes to the mitochondrial matrix. The principle of leader sequence duplication was applied to the protein secretion system of the yeast Saccharomyces cerevisiae and of Bacillus subtilis. The secretion signal sequences of yeast invertase and B. subtilis neutral protease were used to direct the secretion of human interferon alpha 4. Our results show that the duplication of these N-terminal signal sequences does not enhance secretion of interferon alpha 4 in either of the cell systems studied.

Bacillus subtilis↗

PubMed1993

Corticotropin-induced secreted protein, an ACTH-induced protein secreted by adrenocortical cells, is structurally related to thrombospondins.

The treatment of primary cultures of bovine adrenocortical cells with nanomolar concentrations of ACTH induces a 10-fold increase in the synthesis of a secreted protein of apparent molecular mass 195 kDa on reducing SDS-polyacrylamide gels. This corticotropin-induced secreted protein (CISP) appears to be an oligomeric calcium-binding protein. Its secretion under serum-free culture conditions is sustained over 4 days in the continuous presence of ACTH. Induction of CISP secretion by ACTH is mimicked by cAMP analogs and adenylate cyclase activators. We report here the purification of CISP to apparent homogeneity with an overall yield of 43% using a combination of heparin-agarose and Mono-Q chromatographies. The NH2-terminal amino acid sequence and the sequence of several tryptic peptides revealed that CISP is structurally related to the members of the thrombospondin (TSP) family. Among these members, bovine CISP appeared to be more homologous to mouse TSP2 (85% identity in the 29 amino acid long NH2-terminal sequence) than to TSP1 (18% identity in the same region). We also observed that CISP binds Ca2+ and is an adhesive protein for bovine adrenocortical cells. Thus, CISP possesses both structural and functional properties of thrombospondins. Whether CISP represents the bovine form of TSP2 or a novel member of the expanding thrombospondin family will need to be elucidated by cloning and sequencing of a larger portion of the molecule.

Adrenal Cortex↗

PubMed2006

The antiepileptic drug topiramate preserves metabolism-secretion coupling in insulin secreting cells chronically exposed to the fatty acid oleate.

Topiramate (Topamax), primarily prescribed against epilepsy, was reported to reduce body weight and to ameliorate glycemic control in obese patients with diabetes. In rodent models of obesity and diabetes, topiramate treatment counteracts hyperglycemia and increases insulin levels upon glucose tolerance test. These observations suggest that topiramate might exert direct action on insulin secreting cells, in particular regarding obesity associated beta-cell dysfunction. In this study, INS-1E beta-cells were exposed for 3 days to the fatty acid oleate (0.4mM) and concomitantly treated with therapeutic concentrations of topiramate before measurements of insulin secretion and metabolic parameters. In healthy cells, topiramate had no acute or chronic effects on insulin release. Exposure of INS-1E cells to oleate for 3 days increased insulin release at basal 2.5mM glucose and blunted the response to stimulatory glucose concentration (15mM). Such lipotoxic effects were associated with impaired mitochondrial function, as evidenced by partial loss of resting mitochondrial membrane potential and reduced hyperpolarization in response to glucose. Oil-red-O staining and triglyceride measurements revealed lipid accumulation in oleate treated cells. Topiramate treatment counteracted oleate-induced lipid load and partially protected against mitochondrial membrane dysfunction. In particular, topiramate restored glucose stimulated insulin secretion, essentially by maintaining low insulin release at basal glucose. Topiramate increased expression of the nutrient sensor PPARalpha and of the mitochondrial fatty acid carrier CPT-1, correlating with enhancement of beta-oxidation rate. The data demonstrate that a drug originally used as mood stabilizer exerts a direct action on beta-cells, protecting against lipid-induced dysfunction.

Animals↗

PubMed1975

Effects of indomethacin on intestinal secretion, prostaglandin E and cyclic AMP: evidence against a role for prostaglandins in cholera toxin-induced secretion.

The effects of indomethacin on intestine mucosal cAMP, intestinal fluid secretion, and mucosal and fluid PGE were studied in rabbits in vivo following challenge with cholera toxin. Indomethacin had no effect on cholera toxin-induced fluid secretion or cAMP accumulation. Inhibition of PGE synthesis was achieved by the administration of two but not one injection of indomethacin. These studies provide evidence against a role for PGE in mediating cholera toxin-induced secretion and point out the need to measure prostaglandin levels when using prostaglandin synthetase inhibitors in vivo.

Animals↗

PubMed1987

GIP potentiates CCK stimulated pancreatic enzyme secretion: correlation of anatomical structures with the effects of GIP and CCK on amylase secretion.

Utilizing scanning electron microscopy and isolated, vascularly perfused rat pancreas, we studied the angioarchitecture and the effect of the insulinotropic hormone, gastric inhibitory polypeptide (GIP), on cholecystokinin (CCK)-stimulated exocrine secretion. We tried to correlate the microcirculation with the physiological effect of insulin on the pancreatic secretion in the same species. We found a vascular pattern consisting of direct insuloacinar connections, a venous drainage system of islets, and a direct arterial supply of acini. GIP at a concentration as low as 2 ng/ml or exogenous rat insulin potentiated CCK-stimulated pancreatic enzyme secretion. To have similar effects as insulin which is endogenously released by GIP, about 30 times more exogenous rat insulin has to be infused. We conclude that based on the angioarchitecture, insulinotropic hormones like GIP could link the metabolic and the digestive function of the pancreas.

Amylases↗

PubMed1992

Effect of 2-mercaptoethanol on glutathione levels, cystine uptake and insulin secretion in insulin-secreting cells.

The role of glutathione (GSH) in the differentiated state of insulin-secreting cells was studied using 2-mercaptoethanol as a means of varying intracellular GSH levels. 2-Mercaptoethanol (50 microM) caused a marked increase of GSH in two rat insulinoma cell lines, RINm5F and INS-1, the latter being dependent on the presence of 2-mercaptoethanol for survival in tissue culture. The effect of 2-mercaptoethanol on GSH was shared by other thiol compounds. Since in other cell types 2-mercaptoethanol is thought to act on cystine transport, thereby increasing the supply of cysteine for GSH synthesis, we have studied [35S]cystine-uptake in INS-1 cells. At equimolar concentrations to cystine, 2-mercaptoethanol caused stimulation of [35S]cystine-uptake. The effect persisted in the absence of extracellular Na+, probably suggesting the involvement of the Xc- carrier system. INS-1 cells with a high GSH level, cultured 48 h with 2-mercaptoethanol, displayed a lower cystine uptake than control cells with a low GSH content. The effect of variations of the GSH levels on short-term insulin release was studied. No alteration of glyceraldehyde-induced or KCl-induced insulin release in RINm5F cells was detected. In contrast, both in islets and in INS-1 cells, a high GSH level was associated with a slightly lower insulin release. In INS-1 cells the effect was more marked at low glucose concentrations, resulting in an improved stimulation of insulin secretion. On the other hand, in islets, a decrease in the incremental insulin release evoked by glucose was seen. As in other cell types, oxidized glutathione (GSSG) was less than 5% of total GSH, and in INS-1 cells no change in the GSH/GSSG ratio was detected during glucose-induced or 3-isobutyl-1-methylxanthine-induced insulin release. In conclusion, 2-mercaptoethanol-dependent INS-1 cells, as well as RINm5F cells and islets of Langerhans, display a low capacity in maintaining intracellular levels of GSH in tissue culture without extracellular thiol supplementation; 2-mercaptoethanol possibly acts by promoting cyst(e)ine transport; changes in GSH levels caused a moderate effect on the differentiated function of insulin-secreting cells.

Animals↗

PubMed1981

Nervous control of pancreatic endocrine secretion in pigs. V. Influence of the sympathetic nervous system on the pancreatic secretion of insulin and glucagon, and on the insulin and glucagon response to vagal stimulation.

Electrical stimulation of the splanchnic nerves in anesthetized pigs was found to stimulate markedly the pancreatic secretion of glucagon. The response pattern was glucose dependent, the glucagon responses at blood glucose concentrations below 4.5 mmol x l-1 being significantly greater than those noted during stimulation at higher concentrations. Insulin secretion was stimulated weakly and variably and only at higher glucose levels. The magnitude of the glucagon response was comparable to that obtained by electrical stimulation of the thoracic vagus nerves with the same frequency. The glucagon response to combined vagal and splanchnic stimulation was nearly identical to the sum of the responses to the two types of stimulation, whereas splanchnic stimulation abolished or reduced the increase in insulin secretion elicited by vagal stimulation. Combined alpha- and beta-adrenergic blockade markedly reduced the glucagon responses to splanchnic stimulation.

Adrenergic alpha-Antagonists↗

PubMed1992

Pattern of thyrotropin-releasing hormone secretion from the adult and neonatal rat pancreas: comparison with insulin secretion.

In the present study we examined the secretory pattern of pancreatic TRH. TRH is synthesized in the islets of Langerhans as a high mol wt prohormone, which is then processed to give TRH and several putative pro-TRH fragments. The mature TRH was localized in insulin-containing cells of developing rat pancreas, marked by elevated TRH concentrations. The biological role of pancreatic TRH in the regulation of major pancreatic hormones secretion is still poorly understood. We, therefore, studied TRH release from isolated perfused rat pancreas and from neonatal and adult islets in the absence and presence of glucose and arginine to investigate regulation of TRH secretion compared to that of insulin secretion. The secretory pattern of TRH was the opposite of that of insulin in adult pancreas, but was similar to that of insulin in the developing pancreas, suggesting the presence of a subpopulation of beta-cells with peculiar age-dependent topololgy and/or different intracellular transport for TRH. Additionally, antibodies to two pro-TRH-connecting peptides, pro-TRH-(160-169) and pro-TRH-(178-199), were used to characterize the processing in the developing and the adult rat pancreas. There were parallel age-dependent decreases in TRH and both connecting peptides. Interestingly enough, only pro-TRH-(178-199) was selectively released, suggesting that some of the pro-TRH fragments may also assume biological effects. The establishment of these parameters will allow appropriate screening of the biological response to TRH.

Aging↗

PubMed1988

Insulin action and insulin secretion in identical twins with MODY. Evidence for defects in both insulin action and secretion.

To evaluate the pathogenetic mechanisms responsible for development of diabetes in the genetically inherited disease maturity-onset diabetes of the young (MODY), we have investigated a pair of identical twins (19 yr old) from a MODY family. One twin had nondiabetic fasting plasma glucose values but impaired glucose tolerance (IGT), whereas the other suffered from frank diabetes (fasting plasma glucose 12.5 mM). Differences in insulin secretion pattern and/or insulin action between the twins is supposed to be responsible for development of hyperglycemia in MODY. On the other hand, identical defects in insulin secretion and action in the twins may point to the primary genetic defect in MODY. Therefore, our aim was to investigate insulin secretion and insulin action in the twins to find these differences and similarities. We found that fasting plasma insulin and C-peptide values were slightly increased in the twins, whereas the responses of insulin and C-peptide to oral glucose tolerance tests (OGTT) and meals were similar in the twins and within normal range. The insulin responses to OGTT were, however, lower than expected from the glucose values, indicating a beta-cell defect. Despite elevated plasma insulin levels, basal hepatic glucose output (HGO) was normal in the IGT twin but increased by 75% in the diabetic twin. The maximally inhibitory effect of insulin on HGO, when estimated at euglycemia, was normal in the IGT twin but reduced by 60% in the diabetic twin. Furthermore, the maximal insulin-mediated glucose uptake in peripheral tissues was reduced by 40% in the diabetic twin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1995

A defective stimulus-secretion coupling rather than glucotoxicity mediates the impaired insulin secretion in the mildly diabetic F1 hybrids of GK-Wistar rats.

Adult F1 hybrids of male GK and female Wistar control rats exhibit mild, spontaneous non-insulin-dependent diabetes mellitus characterized by impaired glucose-induced insulin secretion. Using isolated pancreatic islets of hybrid rats, we first studied whether impaired glucose-induced insulin response is present not only in adult but also in neonatal rats. Furthermore, we investigated whether the impaired glucose-induced insulin response can be restored by long-term normalization of glycemia. Both 1-week- and 2- to 3-month-old hybrid rats had similar body weights but increased fed blood glucose levels (P < 0.05) compared with age-matched control rats. At 5.5 mmol/l glucose, insulin release was two- to threefold lower in isolated islets of hybrid than in control rats of both age groups (P < 0.05). At 16.7 mmol/l glucose, insulin secretion from hybrid islets was approximately 25% of that from control islets of both 1-week- and 2- to 3-month-old rats. For the second objective, batches of 250 islets from hybrid or control rats were transplanted under the kidney capsule of athymic, normoglycemic nude mice and maintained there for 4 weeks. Perfusion of kidneys demonstrated that glucose-induced (16.7 mmol/l) insulin secretion was impaired markedly in hybrid grafts compared with that in control grafts (0.66 +/- 0.23 vs. 1.8 +/- 0.38 pmol/20 min; P < 0.01), whereas stimulation by 20 mmol/l arginine resulted in similar insulin responses in both groups. The volumes of the grafted islets were similar in kidneys bearing either control or hybrid islets.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1996

Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day.

BACKGROUND: The insulinotropic hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), secreted from the K-cells of the upper small intestine and from the L-cells of the lower small intestine, respectively, are thought to be responsible for intestinal stimulation of insulin secretion. If true, their plasma concentrations should parallel the meal-related diurnal changes in plasma insulin concentrations. METHODS: Using COOH-terminal assays, thought to reflect accurately their rates of secretion, we measured circulating levels of GIP and GLP-1 in six normal subjects for 15 h of a day, during which they ate three mixed meals. RESULTS: Both GIP and GLP-1 concentrations increased significantly and in parallel with insulin in response to all three meals. The plasma insulin concentrations correlated significantly with both GIP and GLP-1 values throughout the study period (correlation coefficients, 0.49 +/- 0.07 and 0.56 +/- 0.05; p < 0.001). CONCLUSIONS: These results support the notion that GLP-1 and GIP are important incretin hormones.

Adult↗

PubMed1979

[Postoperative disturbance in insulin secretion: studies on the altered secretion mode].

1. Depending on the operative trauma, insulin secretion is decreased until the 10th day after abdominal surgery. 2. The decreased insulin release is caused by a diminished discharge from the pancreatic beta cell during the second phase of insulin secretion (partially newly synthesized insulin). Insulin release during the early phase of insulin secretion (prestored insulin) is unchanged or even accelerated. 3. The glucose tolerance level is pathologically diminished until the 10th postoperative day.

Blood Glucose↗

PubMed1996

Ciclazindol inhibits ATP-sensitive K+ channels and stimulates insulin secretion in CR1-G1 insulin-secreting cells.

Ciclazindol, an anorectic drug, was shown to inhibit ATP-sensitive K+ (K(ATP)) channel currents and stimulate insulin secretion from CRI-G1 insulin-secreting cells. In contrast, the structurally related anorectic agent mazindol and the amphetamine-based anorectic compounds diethylpropion, fenfluramine, and phentermine had no effect on K(ATP) channel activity in this cell line. Similarly, cicliazindol elicited insulin secretion from CRI-G1 cells, whereas mazindol had no secretagogue action. The mechanism by which ciclazindol acts to inhibit K(ATP) channel activity is different than that of the sulfonylureas as ciclazindol is effective after procedures that decouple the sulfonylurea receptor from the K(ATP) channel. In agreement with this finding, ciclazindol failed to displace [3H]glibenclamide from CRI-G1 microsomal membranes. Further experiments demonstrated that ciclazindol has no significant effect on voltage-activated currents in this cell line.

Adenosine Triphosphate↗

PubMed2002

TNFalpha-induced macrophage chemokine secretion is more dependent on NF-kappaB expression than lipopolysaccharides-induced macrophage chemokine secretion.

The transcription factor NF-kappaB is a pivotal intracellular regulator of many inflammatory responses and it has been proposed that it represents a potential therapeutic target. As chemokines are important for the progress of an inflammatory response by the recruitment of immuno-competent cells, the role NF-kappaB plays in TNFalpha- or lipopolysaccharides (LPS)-induced chemokine secretion by human monocyte-derived macrophages was examined. Secretion of the CXC chemokines IL-8, GROalpha and ENA-78, induced by TNFalpha, was significantly suppressed by inhibiting NF-kappaB, using overexpression of IkappaBalpha. However, when induced by LPS the expression of these chemokines was unaffected. In contrast, expression of the CC chemokines MIP-1alpha, MCP-1 and RANTES inducedby TNFalpha or LPS was significantly inhibited by the overexpression of IkappaBalpha. Therefore, there appear to be different mechanisms regulating CC and CXC chemokine secretion by macrophages, depending on the stimulus and that TNFalpha and LPS can use different signaling mechanisms in macrophages to regulate chemokine synthesis.

Cells, Cultured↗

PubMed1994

Peyer's patch CD8+ memory T cells secrete T helper type 1 and type 2 cytokines and provide help for immunoglobulin secretion.

Analysis of cytokine gene expression by reverse transcription-polymerase chain reaction (RT-PCR) demonstrated high spontaneous levels of transcripts for multiple cytokines in murine Peyer's patches (PP) compared to spleen and peripheral lymph nodes. This is consistent with the presence of active germinal centers in PP and their continuous exposure to lumenal antigen including bacterial endotoxin. RT-PCR analysis of cytokine transcripts in purified PP T cell populations revealed the presence of transcripts for interleukin-4 (IL-4), IL-5 and IL-10 in addition to interferon-gamma (IFN-gamma) in CD8+ cells purified by flow cytometry. The majority of PP CD8+ T cells were also CD45RBlo (MB23G2-), suggesting that these cells were activated/memory cells. CD8+ cells in spleen and mesenteric lymph nodes (MLN) were predominantly CD45RBhi (MB23G2+) consistent with a resting/naive phenotype. PP and MLN CD8+ T cells also secreted IL-5 and IL-10 when stimulated with anti-CD3 monoclonal antibody and when co-cultured with PP B cells enhanced secretion of both IgG and IgA. These studies suggest that CD8+ T cells at mucosal sites secrete T helper type 2 cytokines and can provide functional help for B cells in these tissues.

Animals↗

PubMed1985

Secretion into the culture medium of a foreign gene product from Escherichia coli: use of the ompF gene for secretion of human beta-endorphin.

The ompF gene codes for a major outer membrane protein of Escherichia coli. A plasmid was constructed in which the structural gene for human beta-endorphin is preceded by the upstream region of the ompF gene consisting of the promoter region and the coding regions for the signal peptide and the N terminus of the OmpF protein. When the plasmid was introduced into E. coli N99, and OmpF-beta-endorphin fused peptide was synthesized and secreted into the culture medium through both the cytoplasmic and outer membranes. The OmpF signal peptide was cleaved correctly during the secretion, indicating that the export of the fused protein across the cytoplasmic membrane was dependent on the signal peptide. The secretion into the culture medium was apparently selective. Neither beta-lactamase nor alkaline phosphatase (both are periplasmic proteins) appeared in the culture medium in significant amounts. The mode of passage of the fused peptide across the outer membrane is discussed.

Bacterial Outer Membrane Proteins↗

PubMed2000

Thrombin induces IL-6 but not TNFalpha secretion by mouse mast cells: threshold-level thrombin receptor and very low level FcepsilonRI signaling synergistically enhance IL-6 secretion.

Mast cells become activated in multiple diseases wherein thrombin generation is often clinically apparent, but the effect of thrombin on cytokine release by mast cells remains unexplored. Thus, we examined IL-6 and TNFalpha release by thrombin-challenged mast cells. Thrombin and the protease-activated receptor (PAR)-1 peptide TRAP(14) induced these cells to secrete IL-6 in a dose-dependent fashion. Mast cells secreted > or =2800 pg IL-6/10(6) cells over 24 h, but only low levels of serotonin and no significant TNFalpha. Furthermore, at near-background levels of allergen, threshold doses of alpha-thrombin synergistically enhanced the IL-6 response (by up to 100-fold), but high-dose costimulation led to a simple additive response. Both the PI(3)- and sphingosine-kinase signaling pathways contributed importantly to the thrombin response. Our data thus clearly demonstrate that low-level thrombin and FcepsilonRI signaling can synergize to augment mast cell IL-6 responses, and that thrombin also differentially induces cytokine secretion by mast cells.

Animals↗