Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study we used a well-characterised model of murine lupus, the female NZB/W hybrid, to study the possible involvement of neuropeptides in the pathogenesis of systemic lupus erythematosus (SLE). Analysis of neuropeptides with a possible role in inflammation showed that substance P (SP) calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) are present in increased quantities in the inflamed kidneys of SLE mice, confirming their involvement in local inflammation, while there is a general reduction in the peptide concentrations in the lymphoid organs of lupus mice, except for NPY. Our results suggest that the altered neuropeptide concentrations observed in the SLE lymphoid organs may be partly responsible for the altered immune response and contribute to the development of autoimmune diseases.
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PMID:Development of systemic lupus erythematosus in mice is associated with alteration of neuropeptide concentrations in inflamed kidneys and immunoregulatory organs. 965 51

Calcitonin gene-related peptide (CGRP) and the preprotachykinin A gene-derived peptides substance P (SP) and neurokinin A (NKA) are expressed in extrinsic primary afferent nerve fibres and intrinsic enteric neurons of the gut. The actions of tachykinins on the digestive effector systems are mediated by three different types of tachykinin receptor, termed NK1, NK2 and NK3 receptors, while the gastro-intestinal actions of CGRP are brought about by CGRP1 and possibly other CGRP receptors. These neuropeptide transmitters are expressed by enteric neurons, intestinal muscle, epithelium and vascular system in a cell-specific manner and enable SP, NKA and CGRP to influence motility, electrolyte and fluid secretion, vascular and immune functions in a peptide- and region-specific fashion. Inflammatory disorders of various aetiology involve changes in the peptidergic innervation of the gut, and inflammatory bowel disease is associated with NK1 receptor upregulation in intestinal blood vessels and lymphoid structures. Some of these alterations are reproduced in experimental models of gastro-intestinal disease, and there is mounting evidence that an imbalanced function of peptidergic neurons contributes to motor, secretory, vascular and immunological disturbances in intestinal anaphylaxis, infection and inflammation. In a therapeutic perspective it seems conceivable that tachykinin and CGRP receptors antagonists can be employed as spasmolytic, antidiarrhoeal, anti-inflammatory and antinociceptive drugs.
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PMID:Implications of tachykinins and calcitonin gene-related peptide in inflammatory bowel disease. 969 97

The autonomic nervous system plays a significant role in liver physiology and pathology. The aim of the present study was to investigate peptidergic nerve fibres in the liver of patients with malignant gastrointestinal tumors that are not metastasizing in this organ. Using light and electron microscopic immunohistochemistry, somatostatin (SOM)-, neuropeptide Y (NPY)-, substance P (SP)- and calcitonin gene-related peptide (CGRP)-immunoreactive (IR) nerve fibres (NF) were detected in the portal tract and perisinusoidally. Histologically, the liver showed dilated sinusoids, filled with lymphoid cells, and scarcely marked perisinusoidal fibrosis. Neuropeptide-IR NF were found in close contact with hepatic sinusoids. Numerous IR varicosities were detected in the sinusoidal wall. We discuss the origin and role of these NF in the liver. Probable quantitative changes in peptidergic NF ensue the inflammatory reaction in sinusoids in malignant gastrointestinal tumors. This could also reflect the increased exposure of the liver to toxic substances in the portal blood flow.
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PMID:Peptidergic nerve fibres in the human liver. 971 62

Reciprocal communication between the immune system and the neuroendocrine system is mediated via a common chemical language of shared ligands and receptors. The neuropeptide substance P (SP) has been implicated as a mediator of immunomodulation. The evidence for substance P receptors on human lymphocytes is, however, controversial. The aims of the present study are to investigate substance P receptor (SPR) expression in human peripheral and mucosal mononuclear cells and to identify cellular sites of expression in human colonic mucosa. Using reverse-transcriptase PCR, we demonstrate that PBMC isolations are negative for SPR mRNA expression, whereas lamina propria mononuclear cell (LPMC) isolations express on average eight SPR mRNA transcripts per cell. In situ hybridization performed on surgically resected colonic tissue confirms the expression of SPR mRNA in LPMC in vivo. SPR mRNA signal was detected in LPMC, lymphoid follicles, and epithelium. The complementary technique of immunohistochemistry gave a similar distribution of SPR expression that colocalized with CD45 immunoreactivity. Dual-fluorochrome flow cytometry revealed SPR expression by CD4, CD45RO, CD45RA, CD8, CD19, and CD14 LPMC subsets, but not PBMC. Our findings suggest that SPR expression is distinctive of human colonic mucosal mononuclear cells and support a direct role for SP in mucosal immunomodulation.
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PMID:Substance P (neurokinin-1) receptor is a marker of human mucosal but not peripheral mononuclear cells: molecular quantitation and localization. 972 16

More than 20 years have passed since the concept that the skin has its own associated immune system was first proposed by Streilein. This proposal was advanced in part on evidence that cutaneous contact hypersensitivity (CH) reactions are closely correlated with Langerhans cells (LC). Recent reports have demonstrated that LC have neural connectivity with cutaneous nerve termini containing calcitonin gene-related peptide (CGRP), suggesting that a link exists between innervation and immune responses in the skin. Here we discuss the neural components which have recently been found to be participants in skin-associated lymphoid tissue (SALT). In part, discovery of a functional link between the nervous system and SALT is based on studies in which cutaneous immunity was impaired by ultraviolet-B radiation (UVR). The deleterious effects of UVR on cutaneous immunity include failed CH induction and promotion of hapten-specific tolerance, effects that are mediated by tumor necrosis factor-alpha and interleukin-10, respectively. The source of these cytokines after UVR appears to be dermal mast cells. Evidence indicates that mast cells are triggered to release these cytokines in response to CGRP, which is released from UVR-damaged cutaneous nerve endings. Moreover, a substance P agonist was able to reverse the deleterious effects of UVR on CH induction, rendering the mice able to develop intense CH. These observations indicate that two cell types not originally included in the SALT concept are critical to the functional integrity of cutaneous immunity: mast cells and cutaneous nerves. We propose that cutaneous nerves dictate whether antigen applied to or arising within skin will lead to sensitivity or tolerance.
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PMID:A new concept of skin-associated lymphoid tissue (SALT): UVB light impaired cutaneous immunity reveals a prominent role for cutaneous nerves. 1020 15

With its abundance of neurons and immunocytes, the gut is a potentially important site for the study of the interaction between the nervous and immune systems. Using immunohistochemical techniques, we tested the hypothesis that gut-associated lymphoid tissue in the porcine small intestine might receive catecholaminergic, cholinergic and peptidergic innervation. Antibodies against protein gene product (PGP) 9.5 were employed to detect neuronal membranes; antibodies against tyrosine hydroxylase (TH), type 2 vesicular monoamine transporter (VMAT-2) and choline acetyltransferase (ChAT) were used to detect catecholaminergic and cholinergic neurons; and antibodies to neuromedin U-8 (NMU-8), substance P (SP) and vasoactive intestinal peptide (VIP) were also used. PGP9.5-immunoreactive nerve fibers were observed between jejunal Peyer's patch (PP) follicles and in submucosal ganglia localized at the base of continuous ileal PP. Many ChAT-positive and a few TH-/VMAT-2-immunoreactive neurons or axons adjacent to jejunal and ileal PP were observed. Neurons and fibers from ganglia situated between or at the base of PP follicles manifested robust immunoreactivities to VIP and NMU-8; relatively less SP immunoreactivity was observed at these locations. All neuromedin-U 8-positive neurons observed exhibited immunoreactivity to ChAT as did some VIP-positive neurons. The specific chemical coding of enteric neurons in close apposition to jejunal and ileal PP and the differential localization of neuropeptides within the jejunal and ileal PP are indicative of neuroimmunomodulation at these sites.
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PMID:Catecholaminergic, cholinergic and peptidergic innervation of gut-associated lymphoid tissue in porcine jejunum and ileum. 1057 Nov 16

Vasoactive intestinal peptide (VIP) and the structurally related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), produced and/or released in the lymphoid microenvironment act primarily as macrophage- and T cell-deactivating agents. In the present study we investigate the effect of VIP and PACAP on the production of TGF-beta1 in the macrophage cell line Raw 264.7 and in peritoneal macrophages. The two neuropeptides do not affect the baseline TGF-beta1 production by unstimulated macrophages, but reduce dramatically TGF-beta1 production by LPS-stimulated macrophages. The effects are mediated through the specific receptors VPAC1, VPAC2, and PAC1. The effect of VIP is mediated primarily through the cAMP pathway, whereas PACAP activates both the cAMP and the protein kinase C pathway. VIP reduces the TGF-beta1 steady-state mRNA levels in both peritoneal macrophages and Raw 264.7 cells treated with LPS. A similar effect is observed upon the in vivo administration of VIP. This report adds VIP and PACAP to the only other neuropeptide, substance P, known to regulate TGF-beta1 production in immune cells.
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PMID:Vasoactive intestinal peptide (VIP) inhibits TGF-beta1 production in murine macrophages. 1080 55

Membrane peptidases are a group of ectoenzymes with a broad functional repertoire. In protein metabolism, their importance is well known, especially in peptide degradation and amino acid scavenging at the intestinal and renal brush border. However, they also perform more subtle tasks; not only do they provide or extinguish signals by cleaving exterior peptide mediators, but they also may function as receptors or participate in signal transduction or in adhesion. Dipeptidyl peptidase IV (DPPIV), which is identical to the lymphocyte surface glycoprotein CD26, is unique among these peptidases because of its ability to liberate Xaa-Pro and less efficiently Xaa-Ala dipeptides from the N-terminus of regulatory peptides. It occurs in the plasma membrane as a homodimer with a total molecular mass of 22-240 KdA and the C-terminal domain probably forms on alpha/beta hydrolase fold. In addition to, but independent of its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase. The in vivo expression on epithelial, endothelial and lymphoid cells of DPPIV is compatible with a role as physiological regulator of a number of peptides that serve as biochemical reporters between and within the immune and neuroendocrine system. Surprisingly, not cytokines with a N-terminal Xaa-Pro motif, but a number of chemokines have recently been identified as substrates. Despite DPPIV mediates only a minimal N-terminal truncation, important alterations in chemokine activities and receptor specificitIes were observed in vitro together with modified inflammatory and antiviral responses. Most probably the great flexibility of the N-terminus of a number of chemokines facilitates the accessibIlity to the catalytic site of DPPIV. Other known substrates which are subject in vitro to receptor-specific changes induced by DPPIV truncation include neuropeptides such as substance P, peptidE YY and neuropeptide Y. On the other hand, DPPIV mediated cleavage of the N-terminal His-Ala or Tyr-Ala dipeptides from circulating incretin hormones like, glucagon-like peptides (GLP)-1 and -2, gastric inhibitory polypeptide (GIP), all members of the enteroglucagon/GRF superfamily, results in their biological inactivation in vitro and in vivo. Administration of specific DPPIV inhibitors closes this pathway of incretin degradation and greatly enhances insulin secretion. The improved glucose tolerance in several animal models for type II diabetes points to specific DPPIV inhibition as a pharmaceutical approach for type 2 diabetes drug development.
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PMID:Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery? 1128 88

Information about the expression of neuropeptide receptors is limited in human peripheral tissues, such as the gastrointestinal tract, as compared to the brain. A detailed evaluation of binding sites for gastrin-releasing peptide (GRP), neuropeptide Y, vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP), gastrin/cholecystokinin, neurotensin, substance P and somatostatin was therefore undertaken in human colon using in vitro receptor autoradiography and subtype characterization with receptor-selective ligands. GRP receptors, Y2 receptors, PACAP type1-receptors, cholecystokinin-A receptors, neurotensinl and sst2 receptors were abundantly expressed in the myenteric plexus. Y2, neurotensinl and sst2 receptors were also strongly expressed in the submucosal plexus. Furthermore, expression of GRP receptors, neurokinin (NK)1 receptors, VIP type2-receptors and sst2 receptors was found in the mucosa-directed margin of the circular smooth muscle where the interstitial cells of Cajal are located. A variable and complementary expression of GRP receptors, VIP/PACAP receptors, Y2 neurotensinl, NK1 and somatostatin receptors was found in the circular and longitudinal smooth muscle. NK1 and Y1 receptors were often detected in arteries and veins, while VIP/PACAP and sst2 receptors were found in lymphoid follicles. Y2, VIP type, and sst2 receptors were present in the colonic mucosa. Y2 was strongly expressed in the muscularis mucosae. This study shows that neuropeptide receptors are expressed in high amounts and in highly specific patterns in distinct targets in the human colon, suggesting a major physiological role for these peptides. The data represent the molecular basis to investigate the regulation by neuropeptides of colonic functions and to develop neuropeptide drugs aimed at interacting with these receptors in colonic diseases, such as Hirschsprung's and Crohn's diseases.
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PMID:Localization and characterization of neuropeptide receptors in human colon. 1168 16

Many hormones and some neuropeptides and neurotransmitters play a key role in regulating numerous lymphoid cell functions. In particular, somatostatin (ss), substance P (sp) and vasoactive intestinal polypeptide (vip) appear to be involved in numerous regulating mechanisms of cell activities in the immune system under both physiological and pathological conditions. ss may be produced by lymphoid cells and accessories as part of the immune system. The distribution of somatostatin receptors (ssr) in the normal human thymus has prompted the hypothesis that ss, and probably other neuropeptides, may play an important role in cell homeostasis in this organ, as well as being one of the processes that regulates the maturation of T lymphocytes. The advent of molecular biology has showed a variable expression of ssr on the various T and B cell lines or lines deriving from lymphoma/ leukemia and human myeloma. Using autoradiographic studies, ssr have been predominantly found in lymphoblastic areas of lymphoma, which represent the active part of the tumour. The expression of ssR has been found in vivo and in vitro, also in pathological sites in patients with autoimmune and granulomatous diseases like rheumatoid arthritis and sarcoidosis.
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PMID:[Somatostatin receptors in immune system cells]. 1175 40


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