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 response to axonal injury, noradrenergic sympathetic neurons of the adult superior cervical ganglion (SCG) alter their neurotransmitter phenotype. These alterations include increases in the levels of the neuropeptides, galanin, vasoactive intestinal peptide (VIP), and substance P (SP) and a decrease in the catecholamine biosynthetic enzyme tyrosine hydroxylase (TH). Previous studies have indicated that after axotomy in vivo, leukemia inhibitory factor (LIF) plays an important role in increasing the contents of galanin and VIP in the SCG. In the present study, by examining the time courses of the changes in LIF and neuropeptide mRNA and by using LIF null mutant mice, we have determined that LIF alters neuropeptide content in part by increasing levels of peptide mRNA. In addition, LIF also makes a small contribution to the axotomy-induced down-regulation of mRNA encoding TH and neuropeptide Y, both of which are normally expressed at high levels in the SCG. Finally, by using a LIF-blocking antiserum, this cytokine was found to regulate SP expression in an in vitro axonal injury model. Thus, after axotomy, a single factor, LIF, participates in the down-regulation of peptides/proteins involved in normal neurotransmission and the up-regulation of a group of neuropeptides normally not present in the SCG that may be involved in regeneration.
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PMID:Involvement of leukemia inhibitory factor in the increases in galanin and vasoactive intestinal peptide mRNA and the decreases in neuropeptide Y and tyrosine hydroxylase mRNA in sympathetic neurons after axotomy. 885 62

Knowledge of biochemical and molecular events during burn wound healing may optimize treatment of patients with thermal injuries. Substance P (SP), a neuropeptide present in C fibers of the skin, has been implicated as a mediator of inflammation and wound healing. This neuropeptide induces vasodilitation and vascular permeability by stimulating endothelial cells to round up, vascular smooth cells to relax, and mast cells to release histamine. SP also induces cytokine release by macrophages and neutrophils. Because many of the functions of SP seemed relevant to wound repair in burns, we used immunocytochemistry to characterize SP+ nerve fibers in healing human burn wounds. Deep partial-thickness burns collected from 20 patients at the time of excision and grafting were formalin fixed, paraffin-embedded, sectioned, and labeled with a monoclonal antibody to SP with use of an immunoperoxidase technique. Our tissue samples included normal skin and 20 specimens from postburn days 2 through 49. In normal adult skin, SP+ nerve fibers surrounded vessels throughout the skin and extended from the papillary dermis into the epidermis. SP+ fibers were absent in early wound beds. SP immunostaining did occur in the advancing epidermis, endothelial cells, and mast cells. SP+ fibers could be identified in the deep dermis and subjacent to the advancing epithelium before the wound beds. Maximum numbers of SP+ fibers were present subjacent to the advancing epithelium at 2 weeks after burn injury. After 4 weeks, the distribution of SP+ fibers in reepithelialized areas was similar to that of normal skin. Our data corroborate published reports of SP+ fiber regeneration in guinea pig burns and correlates with clinical observations of pain and pruritus in patients with thermal injuries. The absence of SP+ fibers in the early wounds with SP immunostaining in the epidermis and extracellular matrix suggests that SP may be released from injured nerves and supports neurogenic mediation of inflammation and vasodilitation in early wound repair. Repopulation of the wound beds with SP+ fibers appeared to follow neovascularization originating in the deep reticular dermis and wound edge.
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PMID:Substance P has a role in neurogenic mediation of human burn wound healing. 888 61

Substance P (SP), one of the best characterized neurogenic mediators of immune hyperactivity, stimulates the production of a variety of cytokines, and acts as a general proinflammatory agent inducing proliferation and activation of immune cells Neurokinin 1 receptor (NK-1R), a G-protein-coupled receptor with high affinity for SP, has been cloned from nonlymphoid tissues. Although previous binding studies indicated the presence of high affinity SP receptors on immune cells, recent studies questioned the existence of specific NK-1R on lymphocytes and monocytes. In this study we investigate the expression of the NK-1R gene in murine T lymphocytes and T cell lines. The expression of NK-1R mRNA was determined by reverse transcription polymerase chain reaction (RT-PCR), with two separate sets of specific primers, and by nuclease protection assays. The NK-1R nature of the lymphocytic amplified fragments was confirmed by Southern blots with specific murine brain NK-1R probes. Both T cells lines (EL-4.IL-2 and LBRM-T6G) which were previously shown to respond to SP by increased IL-2 production express NK-1R mRNA constitutively. Normal spleen cells and purified CD4+ T lymphocytes which also responded to SP by increased IL-2 production express NK-1R mRNA. In addition to CD4+ T cells, NK-1R message is also expressed in murine splenic B lymphocytes. Sequencing of the RT-PCR amplified fragments from EL-4.IL-2 cells, purified CD4+ T lymphocytes, and murine brain showed complete identity to the published murine NK-1R sequence. This study indicates that murine CD4+ T lymphocytes possess the molecular template for the production of NK-1R. Together with previous binding studies, and with pharmacological studies regarding the effect of SP and of selective NK-1R antagonists on cytokine production, the present study supports the hypothesis that the response of CD4+ T cells to SP and related tachykinins is mediated through specific NK-1 receptors.
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PMID:Expression of NK-1 receptor mRNA in murine T lymphocytes. 889 59

Superfusion of rat spinal cord slices with rat interleukin-1 beta resulted in a significant enhancement of electrically evoked substance P-like immunoreactivity with a maximal effect (> 2-fold increase) at 0.1 ng/ml, whereas higher concentration (10-50 ng/ml) of the cytokine inhibited (approximately 50%) the release of the neuropeptide. Interleukin-1 beta (0.1 ng/ml) potentiation of substance P-like immunoreactivity release was abrogated by co-perfusion with interleukin-1 receptor antagonist (10-100 ng/ml) or with indomethacin (1 microM). Superfusion of spinal cord with interleukin-1 beta inhibited electrically evoked calcitonin gene-related peptide-like immunoreactivity release. Modulation of substance P-like immunoreactivity release from the spinal cord by interleukin-1 beta may represent a mechanism responsible for the hyperalgesic action of the cytokine characteristic of the inflammatory response.
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PMID:Effect of interleukin-1 beta on the release of substance P from rat isolated spinal cord. 890 Oct 13

The ability of the cellular components of the skin immune system to mount various types of immune responses is largely dependent upon their ability to release and to respond to different signals provided by immunoregulatory mediators such as cytokines and neuropeptides. In principle, almost every cytokine known so far, including interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), colony stimulating factors (CSF) and several growth factors can be detected in the skin under certain physiological or pathological conditions. There is recent evidence that neuropeptides such as substance P, calcitonin-related gene product (CGRP) a.o. as well as neurohormones such as proopiomelanocortin (POMC), which is the precursor of several peptidehormones including melanocyte stimulating hormones (MSH), are present in epidermal cells, cutaneous tumors and inflammatory cells infiltrating the skin. In addition to their well known functions as neurotransmitters or hormones, these peptides have recently been recognized as potent immunomodulating agents which inhibit the production and activity of immunoregulatory and proinflammatory cytokines (IL-1, IL-2, IFN gamma) but induce the release of factors, e.g., IL-10, which downregulate immune responses. Accordingly, in animals, alpha MSH and CGRP have been shown to inhibit the induction of contact hypersensitivity reactions. Therefore, a complex network of interacting mediators including cytokines and neuropeptides within the cutaneous microenvironment are crucial elements of the induction, elicitation and regulation of cutaneous immune responses.
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PMID:Regulation of the immune response by epidermal cytokines and neurohormones. 890 47

Current evidence indicates that the neuroendocrine system is the highest regulator of immune/inflammatory reactions. Prolactin and growth hormone stimulate the production of leukocytes, including lymphocytes, and maintain immunocompetence. The hypothalamus-pituitary-adrenal axis constitutes the most powerful circuit regulating the immune system. The neuropeptides constituting this axis, namely corticotrophin releasing factor, adrenocorticotrophic hormone, alpha-melanocyte stimulating hormone, and beta-endorphin are powerful immunoregulators, which have a direct regulatory effect on lymphoid cells, regulating immune reactions by the stimulation of immunoregulatory hormones (glucocorticoids) and also by acting on the central nervous system which in turn generates immunoregulatory nerve impulses. Peptidergic nerves are major regulators of the inflammatory response. Substance P and calcitonin gene-related peptide are pro-inflammatory mediators and somatostatin is anti-inflammatory. The neuroendocrine regulation of the inflammatory response is of major significance from the point of view of immune homeostasis. Malfunction of this circuit leads to disease and often is life-threatening. The immune system emits signals towards the neuroendocrine system by cytokine mediators which reach significant blood levels (cytokine-hormones) during systemic immune/inflammatory reactions. Interleukin-1, -6, and TNF-alpha are the major cytokine hormones mediating the acute phase response. These cytokines induce profound neuroendocrine and metabolic changes by interacting with the central nervous system and with many other organs and tissues in the body. Corticotrophin releasing factor functions under these conditions as a major co-ordinator of the response and is responsible for activating the ACTH-adrenal axis for regulating fever and for other CNS effects leading to a sympathetic outflow. Increased ACTH secretion leads to glucocorticoid production. alpha-melanocyte stimulating hormone functions under these conditions as a cytokine antagonist and an anti-pyretic hormone. The sympathetic outflow, in conjunction with increased adrenal activity. leads to the elevation of catecholamines in the bloodstream and in tissues. Current evidence suggests that neuroimmune mechanisms are essential in normal physiology, such as tissue turnover, involution, atrophy, intestinal function, and reproduction. Host defence against infection, trauma and shock relies heavily on the neuroimmunoregulatory network. Moreover, abnormalities of neuroimmunoregulation contribute to the aetiology of autoimmune disease, chronic inflammatory disease, immunodeficiency, allergy, and asthma. Finally, neuroimmune mechanisms play an important role in regeneration and healing.
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PMID:The immune effects of neuropeptides. 891 48

Dramatic changes occur in neuropeptide expression in sensory and sympathetic neurons following axonal injury. Based on the finding that the cytokine leukemia inhibitory factor (LIF) plays an important role in mediating these changes in sympathetic neurons, its participation in triggering changes in sensory neurons was examined. By the use of transgenic mice in which the LIF gene had been knocked out, LIF was found to contribute to the induction of galanin expression in dorsal root ganglia (DRG) after sciatic nerve lesion. On the other hand, two other neuropeptide changes that occur in DRG under these conditions, the reduction of substance P and induction of neuropeptide Y, were independent of LIF expression. In the sympathetic superior cervical ganglion, transection of the postganglionic nerves close to the ganglion resulted in a rapid induction of LIF mRNA in the ganglion and in the lesioned nerve trunk. In contrast, transection of the sciatic nerve close to or distant from the DRG caused a rapid induction of LIF mRNA in the lesioned nerve, but not in the DRG. DRG were capable of making substantial amounts of LIF mRNA when placed in explant cultures, but, in vivo, only a slight induction was found even when both central and peripheral nerve processes of these sensory neurons were transected. These latter observations suggest that, in contrast to the superior cervical ganglia, the DRG environment inhibits the lesion-induced expression of LIF in vivo and/or explanted DRG produce stimulatory signals not found in vivo. Together with the data on the induction of galanin, these observations provide evidence that LIF, generated at a site at some distance from the ganglion, is involved in triggering part of the cell body reaction in sensory neurons.
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PMID:Leukaemia inhibitory factor induced in the sciatic nerve after axotomy is involved in the induction of galanin in sensory neurons. 892 14

Substance P (SP) released by cutaneous C fibres is involved in the physiopathology of cutaneous lesions. As normal human keratinocytes have been reported to express SP receptors, we studied the effects of SP on keratinocyte activation markers such as ICAM-1 induction and cytokine production. Human keratinocytes derived from skin obtained during plastic surgery were cultured in defined medium (MCDB 153) and were stimulated by SP. Flow cytometry analysis showed that SP (10(-7) and 10(-5) M) as well as the specific NK1 agonist Sar9Met(O2)11SP (Sar Met) induced a slight but significant expression of ICAM-1 at the cell surface during treatment periods of 24 h and 48 h. SP (10(-5) M) also induced a significant but transient increase in the production of IL-1alpha, IL-1beta, IL-1 receptor antagonist and IL-8 which was detectable by ELISA techniques 6 h after stimulation. This elevation returned to constitutive levels 24 or 48 h postinduction. TNFalpha secretion was detected in stimulated cells only after 48 h. These results suggest that SP can activate keratinocytes and support its role in the local inflammatory reaction.
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PMID:Substance P and keratinocyte activation markers: an in vitro approach. 893 86

We have recently shown that substance P (SP) participates in the stress-induced modulation of elicited, peritoneal macrophage function. This study reports the in vitro effects of SP on macrophage activity. We show by an MTT bioassay that SP significantly increases cellular metabolic activity. We show by ELISA that preincubating (priming) the macrophages with SP, prior to the incubation with lipopolysaccharide (LPS), results in a significant enhancement of proinflammatory cytokine secretion, relative to LPS alone. Finally, we show that somatostatin can antagonize the SP-induced enhancement of cytokine secretion. The above results demonstrate the importance of the temporal sequence in which stimuli are administered, in vitro, and indicate that SP can act as first signal in the cascade of macrophage activation. We postulate that stress, via the secretion of SP and other sensory neuropeptides, may play a role in the pathogenesis of certain inflammatory diseases of unknown etiology.
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PMID:Substance P primes murine peritoneal macrophages for an augmented proinflammatory cytokine response to lipopolysaccharide. 894 30

Schistosome granulomas make substance P (SP). CP96,345 is a nonpeptide SP receptor antagonist active in vivo. Granulomas that form in the presence of SP receptor blockade produce little IgM as compared to normal lesions. The objective of this study was to determine how CP96,345 modulates granuloma IgM production. Schistosome ova were embolized to the lungs of infected mice to induce granulomas of synchronous age. Animals received CP96,345 (50 mg/kg/day) for 4 days following egg embolization. Then granulomas were isolated from tissue and dispersed into single-cell preparations. The dispersed granuloma cells were cultured in vitro to measure IgM and cytokine secretion. Also, granuloma B cells were studied using an IgM ELISPOT assay and flow cytometry. As expected, mice treated with CP96,345 formed granulomas that secreted little IgM. Granulomas from CP96,345-treated mice, as compared to buffer-treated animals, contained few IgM-secreting B lymphocytes, but had appropriate numbers of B cells expressing surface IgM. Also decreased was the capacity of the granulomas to make IFN-gamma, IL-4, IL-5 and IL-6. CP96,345 treatment did not affect splenocyte IgM or cytokine synthesis. These data suggest that CP96,345 inhibits granuloma IgM secretion by blocking intragranuloma B cell maturation at a terminal stage of B cell differentiation. Moreover, SP receptor antagonist affects a variety of cytokine circuits that could influence IgM B cell maturation in vivo.
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PMID:Substance P receptor antagonist inhibits murine IgM expression in developing schistosome granulomas by blocking the terminal differentiation of intragranuloma B cells. 896 2


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