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

Many studies have shown that tumor necrosis factor (TNF) is a potent soluble mediator of immunoregulation and inflammation. Neuropeptide substance P (SP) has been known to exert significant influence on production of certain inflammatory cytokine by immune cells. Immunopathogenic mechanism underlying the effect of neuropeptide substance P (SP) and the specific amino acid sequence of SP that induces TNF has not been clearly studied. Employing ex vivo and in vitro model systems, we investigated the direct effect of different sequences of SP on TNF secretion by whole blood and separated total mononuclear cells. Aliquots of blood samples (1 ml) or Ficoll-Hypaque-separated total mononuclear cells (1 x 10(6)/ml) were cultured with different concentrations of SP and its sequences (SP 1-4, SP 4-11) or vasoactive intestinal peptide (VIP) for 24 hr at 37 degrees C. Plasma samples and culture supernatants were assayed for TNF levels in a bioassay using a TNF-sensitive WEHI 164 subclone 13 cell line. Plasma from blood samples or lymphocytes treated with whole SP and SP 4-11 at 10(-7), 10(-8), and 10(-9) M concentrations induced significant production of TNF compared to negligible levels of TNF produced by SP 1-4-treated and untreated cultures. VIP at all concentrations tested did not induce TNF production and was similar to untreated control cultures. Separated mononuclear cells also produced significant levels of TNF in response to SP and SP 4-11. Anti-TNF-alpha antibodies neutralized the TNF induced by SP 4-11 in plasma. These studies suggest that an ex vivo system using whole blood may be an ideal model to study the effects of SP on TNF production. These studies also demonstrated that the TNF inducing activity of SP residues in the region containing amino acids 4 to 11.
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PMID:Substance P induces tumor necrosis factor in an ex vivo model system. 749 30

The neuropeptide, substance P (SP), can stimulate secretion of TNF-alpha from macrophages. Neuroglia have SP receptors and subserve various macrophage-like functions in the central nervous system. We investigated whether SP stimulates secretion of TNF-alpha from primary cultures of neuroglial cells containing both astrocytes (approximately 90%) and microglia (approximately 10%). SP alone had no effect; however in the presence of LPS (10 ng/ml), SP (1 to 10 nM) caused a dose-dependent increase in TNF-alpha secretion above the level measured in response to LPS alone. The effective doses of SP correlated with 125I-labeled Bolton Hunter-conjugated SP binding (Kd 0.2 nM) to these cultures. Incubation with LPS did not change the number or affinity of SP-binding sites. In cultures enriched for microglia (> 99% pure), LPS stimulated the secretion of TNF-alpha but SP caused no enhancement. Microglia have no detectable 125I-labeled Bolton-Hunter-conjugated SP binding sites in the presence or absence of LPS. These results indicate that the action of SP is mediated through astrocytes. We investigated whether IL-1 mediates the SP enhancement of TNF-alpha secretion. Addition of IL-1-neutralizing antisera to mixed cultures stimulated with both LPS and 10 nM SP decreased TNF-alpha secretion to the level observed with LPS alone. LPS alone stimulated the secretion of IL-1 in a dose-dependent manner in the primary cultures, and this LPS-mediated IL-1 secretion was enhanced by SP. This enhancement was not observed in microglial cultures. SP may therefore play a role in neuropathologies in which these cytokines have been implicated.
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PMID:Substance P enhances the secretion of tumor necrosis factor-alpha from neuroglial cells stimulated with lipopolysaccharide. 750 35

The immune cytokine interleukin-1 (IL-1) causes a pronounced elevation in substance P (SP) immunoreactivity and the mRNA coding for its preprotachykinin precursor in cultured superior cervical (sympathetic) ganglia (SCG; Jonakait and Schotland, 1990; Freidin and Kessler, 1991; Hart et al., 1991). In this study we have investigated the possibility that the SCG can respond to other immune stimulators, notably lipopolysaccharide (LPS), a product of bacterial cell walls. LPS treatment of cultured SCG resulted in a dose-dependent increase in SP. However, LPS did not induce SP in the absence of non-neuronal cells, suggesting the necessity of a non-neuronal cell-derived intermediate. Since the LPS induction of SP was partially blocked by a specific IL-1 receptor antagonist (IL-1ra) and since LPS induced approximately an 8-fold increase in mRNA coding for IL-1 itself, we concluded that IL-1 is at least one of these LPS-induced intermediates. TNF-alpha, which also raises SP levels, may be another. IL-6, which may also be increased by LPS, does not increase levels of SP. The synthetic glucocorticoid hormone dexamethasone (DEX) blocks the LPS induction of SP with a Ki approximating 8 x 10(-11) M. The inhibition is due in part to the blockade of the LPS induction of ganglionic IL-1 mRNA. Moreover, inhibition of the LPS induction of SP by indomethacin implies mediation of the effect through prostaglandins. The inhibition by indomethacin suggests a non-monocytic cell source since prostaglandins are thought to restrict the LPS induction of monocytic IL-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipopolysaccharide induces substance P in sympathetic ganglia via ganglionic interleukin-1 production. 750 97

Macrophages are supposed to play a key role in inflammatory and tumor angiogenesis. Their importance derives from (1) their ubiquitous presence in normal and especially inflamed tissues, (2) their potential to become activated in response to appropriate stimuli, and (3) their repertoire of secretory products. By release of proteases, growth factors (bFGF, GM-CSF, TGF-alpha, IGF-I, PDGF, VEGF/VPF, TGF-beta), and other monokines (IL-1, IL-6, IL-8, TNF-alpha, substance P, prostaglandins, interferons, thrombospondin 1), activated macrophages have the capability to influence each phase of the angiogenic process, such as alterations of the local extracellular matrix, induction of endothelial cells to migrate or proliferate, and inhibition of vascular growth with formation of differentiated capillaries. This review describes macrophage physiology and the influence of macrophage secretory products on the different phases of angiogenesis in vitro and in vivo.
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PMID:Macrophages and angiogenesis. 750 44

Airway responsiveness is increased in a variety of airway diseases. To understand the mechanism of enhanced airway responsiveness, in particular as it pertains to asthma, animal models have been developed and extensively explored. The guinea pig and Basenji-greyhound dog are the best characterized animals showing airways hyperresponsiveness and appear to bear substantial resemblances to asthmatic human subjects. Challenge with bronchoconstrictive agonist results in bronchoconstriction and transient vascular leak. Both phenomena contribute to the degree of airway narrowing. Adenosine challenge tests not only the responsiveness of the airways, but also that of the airway effector cells such as the mastocyte. Bradykinin and tachykinin cause indirect airway narrowing, probably by liberation of leukotrienes. Responsiveness can be enhanced by immune and non-immune challenges. Ozone, Sephadex, various contractile agonists (leukotriene D-4, bradykinin, platelet-activating factor), as well as certain cytokines (IL-1, IL-2, TNF-alpha) can enhance airway responsiveness. Cyclooxygenase and lipooxygenase products appear to be involved. Allergen-induced hyperresponsiveness is associated with airway inflammation and appears to involve bradykinin and PAF acutely and growth of airway smooth muscle chronically.
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PMID:[Animal models of bronchial hyperreactivity]. 751 8

Ag presentation via the anterior chamber of the eye results in a form of immune deviation termed anterior chamber-associated immune deviation (ACAID). The hallmarks of this response are the suppression of delayed-type hypersensitivity with simultaneous induction of Ab production. In this study, we examined the role of the neuropeptides vasoactive intestinal peptide (VIP) and substance P (SP) and found that the levels of these two peptides are controlled by neurogenic stimulation of the eye by light, and that these molecules determine the outcome of Ag presentation in the eye. Mice reared under diurnal conditions had VIP in the iris and ciliary body (not free in aqueous humor) and low levels of SP. Mice that were reared in the dark (or dark-adapted) did not contain detectable levels of VIP but had high levels of SP. The adaptation of diurnal mice to the dark eliminated VIP and increased SP, while adapting dark-reared mice to the diurnal cycle increased VIP and reduced SP. We then tested the hypothesis that immune reactions resulting from Ag presentation in the eye were linked to SP and VIP. We found that a VIP receptor antagonist, when injected into the eye with Ag, reversed ACAID in diurnal mice, while a SP receptor antagonist restored ACAID to dark-adapted mice. We further determined that injection of Ag or TNF-alpha induced VIP release, while SP was liberated into the aqueous humor following reexposure of dark-reared mice to light. Our results demonstrate a close linkage of intraocular immune reactions to neuropeptide levels in the eye.
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PMID:Neuropeptides modulate immune deviation induced via the anterior chamber of the eye. 754 31

There is increasing evidence that the neurologic system is capable of modulating a wide range of immunologic responses, including certain inflammatory processes in the lung, gastrointestinal tract, and skin. It has been proposed that secreted neuropeptides such as substance P (SP) may mediate these neuroinflammatory interactions by binding to and stimulating immune cells such as mast cells and lymphoid cells. SP is secreted in a variety of tissues by an extensive network of neurosensory C and A5 fibers in response to a wide range of noxious stimuli and injury. Previous studies to examine the effect of SP on mast cells have focused on its role in triggering histamine release and mediating immediate hypersensitivity responses. Recently it was demonstrated that mast cells are also capable of secreting multiple cytokines including TNF-alpha, IL-1, IL-3, IL-4, IL-6, and GM-CSF. In this study we tested the possibility that SP may also influence mast cell-mediated late inflammatory events by modulating the production of one or several of these cytokines. Our results indicate that SP induces TNF-alpha mRNA expression and TNF-alpha secretion in a dose-dependent manner in a murine mast cell line, CFTL12. Likewise, SP stimulates TNF-alpha secretion in freshly isolated murine peritoneal mast cells. The induction of mast cell TNF-alpha is selective, since SP does not stimulate the production of IL-1, IL-3, IL-4, IL-6, or GM-CSF in these cells. The CFTL 12 mast cell line constitutively expresses high levels of SP receptor mRNA which is not modulated by PMA/cycloheximide treatment or SP. These results further support the concept that the neurologic system modulates inflammatory events by neuropeptide-mediated mast cell cytokine release.
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PMID:Substance P selectively activates TNF-alpha gene expression in murine mast cells. 768 20

Human nasal mucosal samples exposed in vitro to substance P or allergenic Ag were tested for the mRNA of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, TNF-alpha, and IFN-gamma using specific reverse transcriptase-polymerase chain reaction assays. After the administration of substance P, at dosages ranging from 10(-6) to 10(-9) M, an enhanced expression of the mRNA for IL-1 beta, -3, -5, -6, TNF-alpha, and IFN-gamma was observed in all mucosal samples of allergic subjects and in half of the nonallergic subjects. The expression of IL-2 and IL-4 was low. Mucosal samples of allergic subjects showed an increased expression of mRNA for cytokines after administration of specific Ag, whereas no enhancement was observed in samples from nonallergic subjects. Our data suggest that substance P may regulate allergic reactions via enhanced production of certain regulatory cytokines.
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PMID:Cytokine expression after the topical administration of substance P to human nasal mucosa. The role of substance P in nasal allergy. 769 47

The embryo expresses paternal antigens foreign to the mother and therefore has been viewed as an allograft. The maternal immune system responds to paternal antigens on the "graft", and these responses are thought to protect pregnancy. However, pregnancy can be aborted by stress, which stimulates local production of TNF-alpha and inhibits TGF-beta 2-producing natural suppressor cell (NS) activity via a neurotransmitter substance P-dependent pathway. Immunization protects against stress-triggered abortion and CD8+ T cells appear to be required. The objective of the present study was to investigate the importance of CD8+ T cells in the prevention of stress-triggered abortion by immunization. Injection of anti-CD8 increased the abortion rate in nonimmunized mice and in immunized mice. Following anti-CD8 injection, stress failed to further increase the abortion rate; a similar high rate of abortion was seen in immunized and anti-CD8-injected mice. These data suggested that stress could act by neutralization and/or elimination of immunoprotective CD8+ T cell function. CD8+ T cells from pregnant mice have been reported to produce a 34-kDa suppressor factor, but we detected a 1.5- to 2-kDa suppressive factor in the HPLC fractions of supernatants obtained from nonstressed decidua, and this activity was abolished by stress and boosted by immunization with Balb/c cells.
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PMID:Inhibition of immunoprotective CD8+ T cells as a basis for stress-triggered substance P-mediated abortion in mice. 880 91

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


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