UNIPROT:P61278 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteolytic cleavage product of complement component 3, (C3a), is like C4a and C5a, is a potent anaphylatoxin and induces the production of inflammatory mediators in phagocytes. Notably, mast cells respond to C3a with the release of vasoactive substances, including histamine. We have examined the function and receptor binding of C3a in a human leukemic mast cell line, HMC-1. Similar to chemoattractant agonists in leukocytes, C3a induced rapid cytosolic free calcium concentration increases in HMC-1 cells. EGTA did not diminish this response, indicating that mobilizable Ca2+ was from intracellular stores. Receptors of C3a in HMC-1 cells couple in part to Bordetella pertussis toxin-sensitive G-proteins and, therefore, appear to belong to the family of serpentine receptors that require G-proteins for signal transduction. HMC-1 cells express two types of C3a receptors, C3aR1 and C3aR2, that were shown to bind 125I-C3a with high-(Kd1 = 2.1-4.8 nM) or low-affinity (Kd2 = 30-150 nM), and both receptors are expressed at high level: 3 x 10(5)-6 x 10(5) C3aR1/cell and 5 x 10(5)-2.3 x 10(6) C3aR2/cell. Results from cross-linking experiments with 125I-C3a fully agree with the presence of two different classes of C3a receptors in HMC-1 cells. Two membrane proteins with apparent molecular masses of 54-61 kDa (p57) and 86-107 kDa (p97) could be covalently modified with 125I-C3a, and this cross-linking was inhibited with an excess of unlabeled C3a. Many of the known agonists for leukocytes including 13 chemokines (IL-8, NAP-2, GRO alpha, ENA-78, IP10, PF4, MCP-1, 2 and 3, RANTES, MIP-1 alpha, MIP-1 beta and I309), three neuropeptides (neuropeptide Y, somatostatin and calcitonin), as well as C5a, did not activate HMC-1 cells, indicating that C3a is one of a few protein ligands for which this cell line expresses specific receptors. The apparent selectivity for C3a and the abundant expression of C3a receptors make the HMC-1 cell line an excellent choice for the cloning of the receptor genes.
...
PMID:Expression of high- and low-affinity receptors for C3a on the human mast cell line, HMC-1. 862 64

The effects of vasoactive intestinal peptide (VIP) on human immunoglobulin (Ig) production were studied in (1) B cell lines; (2) anti-CD40 mAb-stimulated B cells from non-atopic donors; and (3) unstimulated mononuclear cells from atopic patients. In B cell lines, GM-1056, IM-9, and CBL, VIP enhanced IgA1, IgG1 and IgM production, respectively, in a dose-dependent fashion, while the other neuropeptides somatostatin (SOM) or substance P (SP) failed to do so. Among the various cytokines examined including IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, and G-CSF. IL-6 and IL-10 also enhanced Ig production. However, VIP-induced enhancement of Ig production was specific, and was not mediated via these cytokines, since enhancement was blocked by the VIP antagonist, while SOM and SP antagonists, anti-IL-6 mAb, or anti-IL-10 Ab failed to do so. In anti-CD40 mAb-stimulated B cells from nonatopic donors, VIP selectively induced IgA1 and IgA2 production without affecting IgG1, IgG2, IgG3, IgG4, IgM, or IgE production. This stimulatory effect was specifically blocked by the VIP antagonist, but not by SOM or SP antagonists, anti-IL-5 mAb, anti-IL-10 Ab, or anti-TGF-beta Ab. VIP induced IgA1 and IgA2 production by surface IgA1- (sIgA1-) and sIgA2-B cells, respectively, while this agent had no effect on sIgA1+ and sIgA2+B cells. In contrast, in unstimulated mononuclear cells from atopic patients, VIP selectively inhibited spontaneous IgE and IgG4 production without affecting IgG1, IgG2, IgG3, IgM, IgA1, or IgA2 production. This inhibitory effect was specifically blocked by the VIP antagonist, but not by anti-IFN-alpha Ab, anti-IFN-gamma mAb, anti-IL-12 Ab, or anti-TGF-beta Ab. VIP did not inhibit IgE or IgG4 production in B cells or in B cells cultured with either T cells or monocytes. However, VIP inhibited IgE and IgG4 production when B cells were cultured with both T cells and monocytes.
...
PMID:Vasoactive intestinal peptide differentially modulates human immunoglobulin production. 879 Jul 85

The immunosuppressor effects of the widely distributed neuropeptide somatostatin were examined on purified peripheral blood human monocytes. Somatostatin, at concentrations thought to be physiologic (10(-10)-10(-7) M), regulated monocyte/macrophage responses to (LPS) stimulation, as reflected by interleukin production. In particular, somatostatin had direct inhibitory effects on TNF-alpha, IL-1 beta, and IL-6 secretion by LPS-activated monocytes, while the decrease on IL-8 synthesis was modulated mainly by the action of somatostatin on TNF-alpha and IL-1 beta. In fact, the addition of these two inflammatory cytokines to the monocyte culture medium was able to induce IL-8 expression, as demonstrated by mRNA analysis, also in presence of the neuropeptide. Although somatostatin affected IL-8 production in an indirect way, it suppressed directly the chemotactic response of neutrophils to IL-8. Finally, somatostatin downregulation of monocyte activation was confirmed by the decrease of HLA-DR expression on cell plasma membranes (52% versus 33%). Our results confirm that somatostatin exerts preferential effects on the suppression of immunoreactions by modulating cytokine production and activity.
...
PMID:Modulation of cytokine production in activated human monocytes by somatostatin. 892 6

Intestinal epithelial cells secrete proinflammatory cytokines and chemokines that are crucial in mucosal defense. However, this secretion must be tightly regulated, because uncontrolled secretion of proinflammatory mediators may lead to chronic inflammation and mucosal damage. The aim of this study was to determine whether somatostatin, secreted within the intestinal mucosa, regulates secretion of cytokines from intestinal epithelial cells. The spontaneous as well as TNF-alpha- and Salmonella-induced secretion of IL-8 and IL-1beta derived from intestinal cell lines Caco-2 and HT-29 was measured after treatment with somatostatin or its synthetic analogue, octreotide. Somatostatin, at physiological nanomolar concentrations, markedly inhibited the spontaneous and TNF-alpha-induced secretion of IL-8 and IL-1beta. This inhibition was dose dependent, reaching >90% blockage at 3 nM. Furthermore, somatostatin completely abrogated the increased secretion of IL-8 and IL-1beta after invasion by Salmonella. Octreotide, which mainly stimulates somatostatin receptor subtypes 2 and 5, affected the secretion of IL-8 and IL-1beta similarly, and the somatostatin antagonist cyclo-somatostatin completely blocked the somatostatin- and octreotide-induced inhibitory effects. This inhibition was correlated to a reduction of the mRNA concentrations of IL-8 and IL-1beta. No effect was noted regarding cell viability. These results indicate that somatostatin, by directly interacting with its specific receptors that are expressed on intestinal epithelial cells, down-regulates proinflammatory mediator secretion by a mechanism involving the regulation of transcription. These findings suggest that somatostatin plays an active role in regulating the mucosal inflammatory response of intestinal epithelial cells after physiological and pathophysiological stimulations such as bacterial invasion.
...
PMID:Somatostatin through its specific receptor inhibits spontaneous and TNF-alpha- and bacteria-induced IL-8 and IL-1 beta secretion from intestinal epithelial cells. 1097 2

Throughout the body, immune cells of various types, both classical (such as T-cells) and less recognized (such as intestinal epithelial cells) are exposed to a variety of neurotransmitters secreted from local nerve fibers. Moreover, immune cells express specific neurotransmitter receptors. Based on the above we asked whether neurotransmitters. by direct interaction with their receptors, can either evoke or block immune functions in general, and cytokine secretion in particular. We found that several neuropeptides (SOM, Sub P, CGRP and NPY), in nM concentration and in the absence of any additional stimulatory molecules, induced a significant secretion of cytokines from Th0, Th1 and Th2 antigen specific T-cells. Moreover, some neuropeptides surprisingly drove committed Thl and Th2 populations to a 'forbidden' cytokine secretion: secretion of Th2 cytokines from Th1 cells, and vice versa. We further found that SOM by itself markedly affected the secretion of proinflammatory cytokines from intestinal epithelial cells, which play a major role in the gut immunity in the mucosal defense against invading microorganisms. Thus, somatostatin, through its specific receptor, inhibits (> 90%) of the spontaneous, TNF-alpha or bacteria (Salmonella)-induced secretion of IL-8 and IL-1beta from two intestinal epithelial cell lines. Taken together, these observations suggest that neuropeptides can by themselves induce both typical and atypical cytokine secretion from T-cells and intestinal epithelial cells. Since a myriad of immune reactivities are mediated by, and dependent on, specific cytokines secreted from immune cells, the neuropeptide-induced effects may have important implications for numerous physiological and pathological conditions, including autoimmune diseases, chronic inflammation and neoplasias.
...
PMID:Nerve-driven immunity: neuropeptides regulate cytokine secretion of T cells and intestinal epithelial cells in a direct, powerful and contextual manner. 1176 46

Pancreatitis is rightly the most feared complication of endoscopic retrograde cholangiopancreatography (ERCP). Ten percent to 15% of cases of post-ERCP pancreatitis (PEP) are severe by clinical and radiologic criteria. Such cases carry significant morbidity and mortality and are responsible for the vast majority of ERCP-related deaths. The prediction and prevention of PEP have been of great interest to endoscopists since the introduction of ERCP 30 years ago. Prediction and diagnosis of PEP have become more accurate with the widespread availability of serum amylase estimation. A variety of cytokines (eg, interleukin -1, IL-6, and IL-8) and acute phase reactants (eg, C-reactive protein) are also elevated in the serum in acute pancreatitis, and these form the basis of evolving tests for PEP. Urine testing (for amylase) in acute pancreatitis is obsolete, but it may soon undergo a revival in the form of a rapid (3-minute) dipstick test for trypsinogen-2, a sensitive and specific test for this disease. The prevention of PEP takes multiple forms. The following steps are recommended for clinicians: 1) avoid ERCP when other, less invasive or noninvasive imaging tests can do the job (eg, CT or magnetic resonance imaging); 2) avoid high-risk (of PEP) procedures, such as needle-knife papillotomy, balloon dilation of the biliary sphincter, and pancreatic sphincterotomy, and take steps to reduce risk when these procedures are unavoidable; 3) ensure that those who perform ERCP have adequate training and experience; and 4) consider pharmacologic intervention. Despite a depressing catalog of drug interventions that have failed over the years (eg, antihistamines, anticholinergics, and corticosteroids), three agents have recently shown promise: somatostatin; its octapeptide analogue, octreotide; and gabexate mesylate, a protease inhibitor.
...
PMID:Predicting and preventing post-ERCP pancreatitis. 1190 Jun 75

Pancreatic periacinar myofibroblasts are considered to be therapeutic targets for the suppression of acute pancreatitis. To elucidate the mechanisms mediating the therapeutic actions of somatostatin on acute pancreatitis, we investigated how somatostatin affects the tumor necrosis factor (TNF)-alpha-induced interleukin (IL)-6 and IL-8 secretion from pancreatic myofibroblasts. Cytokine secretion was determined by enzyme-linked immunosorbent assay (ELISA) and Northern blotting. Nuclear factor (NF)-kappaB DNA-binding activity was evaluated by electrophoretic mobility shift assay (EMSAs). The expression of somatostatin receptor (SSTR) mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Somatostatin dose-dependently inhibited the TNF-alpha-induced IL-6 secretion. In comparison, the effects on IL-8 secretion were modest. Northern blot analysis demonstrated that somatostatin decreased the TNF-alpha-induced IL-6 mRNA expression, and that this effect was completely blocked by the somatostatin antagonist cyclo-somatostatin. Furthermore, somatostatin suppressed TNF-alpha-induced NF-kappaB activation. These cells bear SSTR subtypes 1 and 2. Somatostatin down-regulated the TNF-alpha-induced IL-6 secretion in human pancreatic periacinar myofibroblasts. These findings suggest that some of the therapeutic actions of somatostatin on acute pancreatitis might be mediated by reducing local IL-6 secretion in the pancreas.
...
PMID:Inhibitory effects of somatostatin on tumor necrosis factor-alpha-induced interleukin-6 secretion in human pancreatic periacinar myofibroblasts. 1206 Aug 57

H. pylori colonisation of the stomach causes the recruitment of the inflammatory cells by the adherence of the bacteria with the epithelium and the release of factors of virulence either to the contact (oipA or other soluble factors) or in the cell by translocation (CagA). Such contact triggers interleukin 8 expression in the epithelial cell and attracts lymphocytes and monocytes into the chorion. Bacterial lipopolysaccharide and urease support the activation of these inflammatory cells. The lymphocytes produce pro-inflammatory cytokines, which direct the immune response towards the Th1 pathway. The variability of the inflammatory response depends on hereditary factors of the host such as the interleukin 1 genotypes, which determine the level of the pro-inflammatory cytokine expression, and of bacterial factors such as the cag pathogenicity island, the lipopolysaccharide and the vacuolating toxin, vacA. The mucosal inflammation provokes apoptosis and atrophy of the epithelial cells through the effect of pro-inflammatory cytokines and free radicals. Epithelial proliferation is a consequence of excessive apoptosis caused by the infection. It is stimulated by the expression of inducible cyclo-oxygenase and inducible nitric oxide synthase. The development of atrophic gastritis towards cancer is supported by nitric oxide which has a mutagenic effect on DNA and inhibits p53 protein and by the bacterium itself which decreases DNA mismatch repairing activity. The gastritis induced by Helicobacter pylori changes acid secretion according to the prevalent location of the gastritis in the antrum or in the gastric body. Prevalent gastritis in the gastric body causes hypochlorhydria by reducing the release of histamin from ECL cells and inhibiting the parietal cells through the effect of tumor necrosis factor and interleukin 1-beta. Hypochlorhydria is more marked among patients having a pro-inflammatory genotype for interleukin 1-beta and those infected by bacteria with virulence factors. In the event of antrum predominant gastritis, the pro-inflammatory cytokines cause a reduction of somatostatin and gastrin releases from the D and the G cells, respectively. The result of all is increased maximal acid output and the meal-stimulated acid secretion.
...
PMID:[What are the gastric modifications induced by acute and chronic Helicobacter pylori infection?]. 1270 Apr 95

Kupffer cells (KC) and lipopolysaccharide (LPS) interaction is the initial event leading to hepatic inflammation and fibrosis in many types of liver injury. We studied chemokine secretion by KC activated with LPS and the possible effect of the somatostatin analogue octreotide, in the regulation of this process. KC isolated from Sprague-Dawley rats were cultured in the presence of LPS added alone or with different concentrations of octreotide for 24 and 48 h, and chemokine production was assessed in culture supernatants by ELISA. CC chemokine mRNA expression was assessed by semiquantitative RT-PCR. Vehicle-stimulated KC produced a basal amount of CC and CXC chemokines. LPS-stimulated KC secreted significantly increased amounts of IL-8 (GRO/CINC-1) (P<0.001), MIP-2 (P<0.001), MCP-1 (P<0.001), and RANTES (P<0.01). Octreotide inhibited LPS-induced secretion of the CC chemokines MCP-1 (P<0.05) and RANTES (P<0.05), but not the CXC chemokines IL-8 (GRO/CINC-1) and MIP-2, in a concentration-dependent manner. Downregulation of basal and LPS-induced mRNA expression of the CC chemokines was also observed in the presence of octreotide. Pretreatment with phosphatidylinositol 3 (PI3)-kinase inhibitors reduced chemokine production by LPS-treated KC in both the mRNA and protein level. Furthermore, it prevented the octreotide inhibitory effect on LPS-induced chemokine secretion, indicating a possible involvement of the PI3-kinase pathway. In conclusion, these data demonstrate that chemokine secretion by KC can be differentially regulated by octreotide, and suggest that this somatostatin analogue may have immunoregulatory effects on resident liver macrophages. British Journal of Pharmacology (2004) 141, 477-487. doi:10.1038/sj.bjp.0705633
...
PMID:Octreotide regulates CC but not CXC LPS-induced chemokine secretion in rat Kupffer cells. 1471 56

Somatostatin (SRIF)-14 is recognized as an important mediator between the nervous and the immune system, although the functional role of its receptors (sst(1)-sst(5)) is poorly understood in humans. In our study, we demonstrate that human macrophages, differentiated from PBMC-derived monocytes, express sst(1) and sst(2) mRNAs. sst(1) and sst(2) are mostly localized at the cell surface and display active binding sites. In particular, sst(1)/sst(2) activation results in a weak internalization of sst(1), and the sst(2) internalization appears more efficient. At the functional level, the activation of SRIF receptors by the multiligand analogs SOM230 and KE108, but not by SRIF-14 or cortistatin-14, reduces macrophage viability. Their effects are mimicked by the selective activation of sst(1) and sst(2) using CH-275 and SMS 201-995/L-779,976, respectively. Further, sst(1)- and sst(2)-mediated effects are reversed by the sst(1) antagonist SRA-880 or the sst(2) antagonist CYN 154806, respectively. CH-275, SMS 201-995, and L-779,976, but not SRIF-14, decrease mRNA expression and secretion of the MCP-1. In addition, SRIF-14, CH-275, SMS 201-995, and L-779,976 decrease IL-8 secretion, and they do not affect IL-8 mRNA expression. In contrast, SRIF-14 and sst(1)/sst(2) agonists do not affect the secretion of matrix metalloproteinase-9. Collectively, our results suggest that the SRIF system, through sst(1) and sst(2), exerts mainly an immunosuppressive effect in human macrophages and may, therefore, represent a therapeutic window that can be exploited for the development of new strategies in pharmacological therapy of inflammation.
...
PMID:Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages. 1714 91

1 2 Next >>