Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The granulomas of mice infected with Schistosoma mansoni for 8 wk have macrophages that secrete somatostatin 1-14 (SOM). Within the granuloma, SOM has no known function. To uncover the possible significance of SOM produced within this granulomatous inflammation, we sought SOM receptors on distinct cellular components of the granuloma to identify cells targeted for SOM action. [125I]SOM 1-14 bound to dispersed granuloma inflammatory cells specifically and reversibly. Scatchard analysis suggested one receptor type (kDa 4.28 x 10(-9) M). Octreotide, a stable SOM derivative, displaced radioligand (kDa 1.01 x 10(-10) M), but SOM 1-28, substance P, and vasoactive intestinal peptide did not. The SOM receptor localized exclusively to a subset of granuloma CD4+ T lymphocytes. Using IL-5 and IFN-gamma ELISA, it was shown that granuloma T cells can secrete appreciable IL-5 and IFN-gamma when stimulated with Ag or mitogen. Both SOM and octreotide at concentrations as low as 10(-10) M substantially decreased IFN-gamma secretion from Ag or mitogen-stimulated T cells, but at concentrations as high as 10(-6) did not affect IL-5 production. Octreotide administered to animals in vivo decreased the intensity of the granulomatous response. Thus, some granuloma T cells have SOM 1-14 receptors. SOM 1-14, a product of granuloma macrophages, may participate in regulation of the granulomatous response by modulating the secretion of some lymphokines. Octreotide, a clinically useful SOM analog, mimics the action of SOM on the immune system.
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PMID:Granuloma T lymphocytes in murine schistosomiasis mansoni have somatostatin receptors and respond to somatostatin with decreased IFN-gamma secretion. 135 73

We studied the effect of vasoactive intestinal peptide (VIP), somatostatin (SOM), and substance P (SP) on IL-4-stimulated human IgE and IgG subclass production. VIP and SOM, but not SP, inhibited IgE production without affecting IgM or IgA production by mononuclear cells (MNC) from nonatopic donors from 10 pM to 10 nM. These neuropeptides also differentially modulated IgG subclass production. While IgG1 production was not affected by VIP, SOM, or SP, all of the neuropeptides enhanced IgG2 production. By contrast, SOM and SP, but not VIP, inhibited IgG3 production, whereas VIP and SP, but not SOM, enhanced IgG4 production. The effect by neuropeptides was specific since each peptide effect was specifically blocked by each antagonist. To achieve this effect, neuropeptides must be added at the start of the culture and be present throughout the entire culture period. The inhibition of IgE production was not mediated by known inhibitors of IgE production, IFN-gamma or PGE2, because the addition of anti-IFN-gamma mAb (10 micrograms/ml) or indomethacin (0.1 microM) did not overcome the inhibition of IgE production. In contrast to MNC, neuropeptides did not affect IgG subclass production in purified B cells. IgE production was not induced by IL-4 in purified B cells. Neuropeptides also failed to modulate IgG subclass production in cultures of B cells with either T cells or monocytes. However, they modulated IgE production and IgG subclass production in B cells in the presence of T cells and monocytes. In purified B cells, IL-4 plus anti-CD40 mAb induced IgE production which was not inhibited by VIP or SOM. However, VIP or SOM, but not SP, inhibited IgE production in B cells cultured with both T cells and monocytes. Finally, the mechanism of modulation of IgE and IgG4 production was dependent on IL-4-induced switching, since neuropeptides modulated IgG4 and IgE production in surface IgG4-negative (sIgG4-) and sIgE- B cells, respectively. In contrast, modulation of IgG2 and IgG3 production was not due to switching, since neuropeptides did not affect either IgG2 or IgG3 production in sIgG2- or sIgG3- B cells, respectively.
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PMID:Differential effect of vasoactive intestinal peptide, somatostatin, and substance P on human IgE and IgG subclass production. 138 70

At present, only islet cell lines of animal origin have been successfully generated (e.g. RIN, HIT). A fully differentiated human beta cell line would be advantageous for diabetes research. We now report the generation of a human endocrine pancreatic cell line obtained by transfection using a plasmid containing the early region of SV40 viral DNA. Viral integration and transcription was assessed by Southern and Northern blotting. This cell line has been growing continuously for more than 2 years and maintains several of the characteristics of the parental cells from which they were generated. The presence of Neuron Specific Enolase, Protein Gene Product 9.5, cytokeratin, microvilli, cytoplasmic electrodense granules and the secretion of insulin, glucagon and somatostatin supports the neuroendocrine origin of this cell line. However, hormone production progressively decreased and finally stopped at passage 8. Flow cytometric analysis showed that HLA expression in this cell line is readily induced by IFN-gamma and modulated by TNF-alpha. The establishment of this human endocrine cell line indicates the feasibility of immortalizing human islets by transfection with viral oncogenes. To obtain a fully differentiated cell line it may be necessary to use other DNA constructs which immortalize the cells without fully transforming their phenotype.
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PMID:Transfection with SV40 gene of human pancreatic endocrine cells. 168 Mar 32

Somatostatin (SMS) is a tetradecapeptide which can inhibit the secretion of a number of peptides produced by the endocrine or nervous systems. SMS 201-995 (octreotide) is a somatostatin analogue with very potent somatostatin activities. We have been investigating the effects of both SMS and octreotide on the production of human interferon (IFN). We obtained human peripheral blood mononuclear cells from normal donors and induced them to produce IFN in the presence or absence of a number of peptides possessing somatostatin activities. SMS and octreotide were shown to inhibit the secretion of INF-gamma but not IFN-alpha. Concentrations of 10(-6) M were shown to decrease yields when Concanavalin A or phytohemagglutin were used as the inducer. Higher concentrations had a progressively greater effect. No effects were observed on IFN-gamma production if interleukin 2, ionomycin, or various natural antigens were used to induce the cells. The 28-amino acid form of somatostatin had some effects on gamma IFN yields but the first 14-amino acid fragment of this peptide moiety did not. No effect of any of these compounds was observed on IFN bioactivity. These studies indicate SMS may have some regulatory action on the secretion of immunomodulators in vitro but the concentrations required are well above those encountered under physiologic circumstances, suggesting SMS may not play an important regulatory role governing such secretion in vivo.
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PMID:The effect of somatostatin on the production of human interferons by mononuclear cells. 169 38

Cytokine effects on permanent cell lines of transformed mouse pancreatic alpha- and beta-cells were compared. The beta-tumor cell 1 (beta TC1) line (from an adenoma created in transgenic mice expressing the SV40 large T-antigen oncogene under control of the rat insulin II promoter) produced insulin predominantly, although small quantities of intracellular glucagon (100:1 insulin to glucagon) were detectable by radioimmunoassay. The alpha TC1 line (from an adenoma created in transgenic mice expressing the SV40 large T-antigen oncogene under control of the rat preproglucagon promoter) produced not only glucagon but also considerable quantities of insulin (4:1 glucagon to insulin) and preproinsulin mRNA. We therefore cloned alpha TC1 cells and obtained 12 glucagon-producing clonal cell lines that did not produce levels of insulin detectable by radioimmunoassay. Analysis by Northern blotting of total RNA from two lines, alpha TC1 clones 6 and 9, confirmed the absence of preproinsulin mRNA. No somatostatin or pancreatic polypeptide was detected by immunohistochemical staining in alpha TC1 clones 6 or 9 or beta TC1 cells. Rat recombinant gamma-interferon (IFN-gamma; 5-250 U/ml) or mouse recombinant interleukin 1 (IL-1; 1-25 U/ml) individually inhibited DNA synthesis in beta TC1 cells after 3 days of treatment. The two cytokines in combination acted synergistically to further depress DNA synthesis and increase cytotoxicity. In contrast, alpha TC1 clone 9 cells were not sensitive to inhibition of DNA synthesis by each cytokine individually, although glucagon synthesis was inhibited. The combination of these cytokines caused marked inhibition of DNA and glucagon syntheses in alpha TC1 clone 9 cells. alpha TC1 clone 9 cells were somewhat more resistant to the cytotoxic action of the combined cytokines than were beta TC1 cells. Incubation with 50 U/ml IFN-gamma induced class II MHC molecules (I-Ab, I-Ad, and I-Ed) and enhanced the constitutive expression of class I molecules (H-2Kb and H-2Kd) on the cell surfaces of beta TC1, uncloned alpha TC1, and alpha TC1 clones 6 and 9. Thus, these cell lines are heterozygous for MHC alleles derived from both parental strains used in the construction of the transgenic mice [C57BL/6J (H-2b) and DBA/2J (H-2d)]. Class II gene transcription induced by IFN-gamma was confirmed in beta TC1 and alpha TC1 clone 9 cells by Northern blot analysis with A alpha-, A beta-, E alpha, and E beta-DNA probes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparison of cytokine effects on mouse pancreatic alpha-cell and beta-cell lines. Viability, secretory function, and MHC antigen expression. 210 69

The immune system and the neuroendocrine system affect each other via molecules and receptors shared by both systems. Neuroendocrine hormones may act either positively or negatively in regulating the activities of a key cell of the immune system, the macrophage. For example, adenocorticotropic hormone (ACTH), somatostatin, and substance P are all capable of increasing the cytotoxicity of macrophages against tumor cells. However, ACTH and somatostatin, but not substance P, can also block the tumoricidal activity of macrophages induced by recombinant gamma interferon (IFN-gamma), a non-neuroendocrine immunomodulating hormone. In contrast, substance P increased tumoricidal activity, both independent of IFN-gamma and in addition to IFN-gamma. Neurotensin, alpha-endorphin, beta-endorphin, met-enkephalin, vasopressin, and substance K did not affect tumoricidal function, either alone or in combination with IFN-gamma. Substance P, but not the other neuropeptides, increased substantially the proportion of macrophages able to secrete superoxide ions, suggesting a possible influence on macrophage capacity to deal with microbial infection. Such positive and negative modulation of macrophage effector functions could contribute to the influence of cognitive stimuli in infection and neoplasia.
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PMID:Neuropeptides modulating macrophage function. 303 73

Substance P (SP) and somatostatin 1-14 (SOM) have immunoregulatory properties. Cells within the granulomas of murine schistosomiasis mansoni make both. SP enhances, whereas SOM inhibits soluble egg Ag (SEA)-induced, IFN-gamma production. IFN-gamma is important during IgG2a isotype switching. Thus, we investigated whether SP or SOM could affect IgG2a production in murine schistosomiasis. Our results show that SEA and rIFN-gamma stimulate splenic IgG2a secretion in murine schistosomiasis. Moreover, SP at > or = to 10(-10) M substantially increased both polyclonal as well as SEA-specific, IgG2a secretion from spleen cells challenged with SEA. However, cells exposed to SOM at > or = 10(-10)M showed strong inhibition. Also, both SP and SOM modulated the frequency of IgG2a-producing cells. Splenic IgG2a production in response to SEA, SP, and SOM required the presence of Thy 1.2+ cells, whereas, rIFN-gamma- induced IgG2a synthesis did not. Also, experiments using irradiation lymphocytes showed that SP, SOM, or rIFN-gamma modulation of IgG2a release was not dependent on cell proliferation. The highly specific SP receptor antagonist, CP-96,345, completely inhibited the effect of SP but not SOM on IgG2a release. This suggests that SP acted through an authentic NK-1 receptor and that SOM required a different receptor interaction. Granuloma cells secreted IgG2a constitutively. Yet, neither SEA, SP, SOM, rIFN-gamma, nor blocking anti-IFN-gamma mAb could modulate this constitutive IgG2a release during short term culture conditions. Moreover, the IgG2a secretion also continued in the absence of Thy 1.2+ lymphocytes. However, mice treated with CP-96,345 or octreotide (SOM agonist) in vivo produced granulomas that made little or no IgG2a. Spleen cell experiments showed that SEA, SP, SOM, and rIFN-gamma could only affect SEA-induced, IgG2a production during early stages of Ag stimulation. Thus, unlike the spleen, it is probable that the granulomas contain mostly activated B cells that have completed switch recombination.
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PMID:Substance P and somatostatin can modulate the amount of IgG2a secreted in response to schistosome egg antigens in murine schistosomiasis mansoni. 750 19

The effect of vasoactive intestinal peptide (VIP), somatostatin (SOM), and substance P (SP) on spontaneous human IgE and IgG4 production in atopic patients was studied. In cultures of mononuclear cells (MNC), VIP inhibited both IgE and IgG4 production without affecting IgM, IgA, IgG1, IgG2, or IgG3 production. In contrast, SOM inhibited only IgE production whereas SP inhibited only IgG4 production without affecting production of other isotypes or other IgG subclasses. The effect of neuropeptides was specific because each was specifically blocked by a corresponding neuropeptide antagonist. To achieve the effect noted above, neuropeptides must be added at the start of the culture. IFN-alpha and IFN-gamma were found to inhibit both IgE and IgG4 production whereas prostaglandin E2 (PGE2) inhibited only IgE production. However, the inhibition of IgE and IgG4 production by neuropeptides could not have been mediated by IFN-alpha, IFN-gamma, or PGE2 because the addition of anti-IFN-alpha, anti-IFN-gamma, and indomethacin, respectively, did not reverse the inhibition. In contrast to their effects on MNC, neuropeptides did not affect production of either IgE or IgG4 by purified B cells; the addition of either T cells or monocytes to B cells had no effect on this. However, neuropeptides were effective in inhibiting IgE and IgG4 production by B cells cultured together with both T cells and monocytes. Depletion of sIgE+ and sIgG4+ B cells resulted in abrogation of IgE and IgG4 production, respectively. However, stimulation of sIgE- B cells with IL-4 plus anti-CD 40 mAb induced IgE production, which was inhibited by VIP and SOM, but not SP, in the presence of both T cells and monocytes. These results suggest that neuropeptides inhibited spontaneous IgE and IgG4 production by interaction with sIgE+ and sIgG4+ B cells in a T cell- and monocyte-dependent fashion. In addition, VIP and SOM also inhibited IgE production by modulating switching induced by IL-4 plus anti-CD 40 mAb in a T cell- and monocyte-dependent fashion.
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PMID:Effect of vasoactive intestinal peptide, somatostatin, and substance P on spontaneous IgE and IgG4 production in atopic patients. 768 25

In murine Schistosomiasis mansoni, granuloma eosinophils make SP. We investigated whether SP affects lymphokine secretion in murine schistosomiasis. SP at > or = 10(-10) M, and other tachykinins at much higher concentrations, substantially increased IFN-gamma secretion from spleen or granuloma inflammatory cells primed in vitro by suboptimal stimulatory concentrations of egg Ag or mitogen. Cells receiving maximal antigenic or mitogenic stimulation were affected marginally. Also, tachykinins induced no IFN-gamma from resting cells receiving no Ag or mitogen stimulation. There are three distinct tachykinin receptors, called NK-1, NK-2 and NK-3. SP binds the NK-1 receptor with highest affinity. Specific NK-1 receptor antagonists blocked all tachykinin-induced, IFN-gamma secretion. An NK-2 receptor inhibitor had no effect. Thus, SP and other tachykinins were acting through an NK-1 receptor. Inflammatory cells from 4-day-old granulomas cultured in vitro secrete IFN-gamma. Yet, there was no measurable IFN-gamma when SP receptor antagonists were added to the cultures. Moreover, animals treated in vivo with the NK-1 receptor antagonist CP-96,345 produced smaller granulomas. This suggested that endogenous SP may be necessary for normal induction of granuloma IFN-gamma secretion and a normal granulomatous response. Granuloma macrophages make somatostatin (SOM) that can decrease IFN-gamma secretion. Yet, IFN-gamma secretion was unaffected when both SP and SOM were in the cell cultures. In conclusion, SP modulates Ag-driven IFN-gamma secretion through a NK-1 receptor. Also, SP and SOM may be components of a natural circuit within inflammation that regulates IFN-gamma production.
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PMID:Substance P modulates antigen-induced, IFN-gamma production in murine Schistosomiasis mansoni. 768 34

Schistosomiasis mansoni is a disease characterized by liver and intestinal granulomas. Previous investigations in our laboratory showed that nylon wool-adherent CD4+ T lymphocytes isolated from murine hepatic schistosome granulomas express receptors for somatostatin 1-14. Moreover, somatostatin 1-14 substantially decreased IFN-gamma and IgG2a, but not IL-5 secretion by dispersed granuloma cells. This paper extends these observations by defining the somatostatin receptor (SSTR) isoform most likely expressed by granuloma inflammatory lymphocytes. Amplification of mRNA by reverse transcription PCR shows SSTR1, SSTR2, and SSTR3 mRNA in normal mouse brain and other tissues. Nevertheless, only the SSTR2 PCR product was amplified from granuloma cell RNA. The nucleotide sequence of the granuloma SSTR2 PCR product from inflammatory cells is identical to the CBA murine brain SSTR2 cDNA sequence. Granuloma-derived T cell lines, FACS-isolated granuloma CD4+ T cells, thymocytes, splenocytes, and cloned T cell lines all contain mRNA for SSTR2 by reverse transcription PCR. Moreover, both SSTR2A and the splice variant SSTR2B can be amplified from dispersed granuloma cells, granuloma T cell lines, thymocytes, and splenocytes. This is the first demonstration that inflammatory cells produce mRNA for an authentic somatostatin receptor. It is probable that the lymphocyte SSTR2 receptor mediates somatostatin-induced modulation of IFN-gamma secretion.
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PMID:T lymphocytes isolated from the hepatic granulomas of schistosome-infected mice express somatostatin receptor subtype II (SSTR2) messenger RNA. 791 11


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