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

In previous work we reported the elevation of circulating inflammatory cytokines in rodents maintained on a Mg(2+)-deficient diet. Within the first week of Mg2+ deficiency, significant elevation of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) occurs. The present study was designed to assess the effects of SP receptor blockade by CP-96,945 and its inactive enantiomer CP-96,344 on tissue cytokine levels and in vivo oxidative indexes. CP-96,345 had no significant effect on circulating levels of SP or CGRP; however, at the tissue level, a significant decrease (P < .01) in myocardial accumulation of SP occurred; the inactive enantiomer was only slightly effective. In addition, CP-96,345 significantly reduced (by 53%) the accumulation of tumor necrosis factor-alpha (TNF-alpha) (but not interleukin-1 and interleukin-6) within the lesions; the effect of the enantiomer was insignificant. We conclude that treatment with CP-96,345 inhibits SP and TNF-alpha tissue levels in cardiac lesions, indicating a linkage between this neuropeptide and TNF-alpha. Both SP and TNF-alpha can trigger free radical production; plasma thiobarbituric acid-reactive materials were elevated 2.5-fold and red blood cell reduced glutathione was reduced 55% during Mg2+ deficiency. In the presence of CP-96,345, both indexes of in vivo oxidation were significantly attenuated; the enantiomer was ineffective. These latter observations point to a neuropeptide/TNF-alpha/free radical-triggered mechanism that may be the major pathway of systemic oxidative injury inducing the cardiomyopathic lesions seen during Mg2+ deficiency.
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PMID:Blockade of cardiac inflammation in Mg2+ deficiency by substance P receptor inhibition. 751 52

We demonstrate that morphine, at higher concentrations than that effective in the inhibition of spontaneously active cells, can antagonize stimulation of human granulocytes by tumor necrosis factor (TNF) or substance P. The antagonistic effect appears to occur indirectly by way of downregulation of the cells' responsiveness to these stimulatory substances. We have previously shown that neutral endopeptidase 24.11 (NEP) is an important enzyme in neuro- and autoimmunoregulation of both vertebrates and invertebrates, and that activation of human granulocytes by monokines and neuropeptides results in regulation of NEP. Exposure of intact human granulocytes to morphine increases NEP by a naloxone-sensitive mechanism. The increased expression of NEP downregulates the stimulatory effect of substance P and TNF. In the case of substance P, we demonstrate the significance of NEP in modulating the process of downregulation by use of a specific NEP inhibitor, phosphoramidon. These results indicate that morphine is a significant factor in downregulating immunocyte responsiveness to NEP substrates and also to those signal molecules (i.e. cytokines) not metabolized by it. In summary, we infer that opiates may be endogenous signal molecules, a status that appears to be amply supported by their immunosuppressive actions.
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PMID:Inhibitory effect of morphine on granulocyte stimulation by tumor necrosis factor and substance P. 751 78

There is increasing evidence that neuropeptides, steroid hormones and inflammatory cytokines influence the immune response during the reproductive cycle. In the present study, we focus on the effects of neuropeptide Substance P (SP) during the pre-implantation stage of embryo development (day 4 of pregnancy), at pro-estrus and di-estrus (two phases with different hormonal states). We found heterogeneous responses to SP and anti-IgE by the rat uterine mast cells (MCs), as detected by ELISA. In fact, MCs purified from uteri on day 4 of pregnancy released histamine, granulocyte macrophage-colony stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) in response to anti-IgE, but not to SP. When pre-incubated with SP, the release to anti-IgE was significantly enhanced compared to anti-IgE alone. Exposure of SP to antibodies to SP, prior to pre-incubation with MCs, negated the SP effect on IgE-mediated release. At the pro-estrus phase SP showed similar behavior as on day 4 of pregnancy, whereas at the di-estrus phase SP alone was capable of inducing release of histamine and cytokines from purified uterine MCs. Moreover, non-quantitative RT-PCR analysis of the TNF-alpha mRNA level suggested an SP stimulation at the di-estrus phase, but neither on day 4 of pregnancy nor at the pro-estrus phase. Taken together, these data strongly suggest that SP can modulate IgE-mediated uterine MC release of histamine and inflammatory cytokines in different ways, depending on the phase of the reproductive cycle.
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PMID:Effect of substance P on uterine mast cell cytokine release during the reproductive cycle. 754 5

Glucocorticoids are potent antiinflammatory agents. They inhibit leukocyte chemotaxis and vascular permeability and generally suppress the expression of many inflammatory mediators. Recent reports suggested that somatostatin (Sms) had significant immunomodulatory properties in vitro and in vivo. In this study we examined the effects of glucocorticoids on immunoreactive somatostatin expression in aseptic inflammatory sites of Sprague-Dawley rats given carrageenin sc. The progress of the inflammatory reaction was studied over a 7-h period with respect to the volume and cellularity of the exudate and the levels of the inflammatory mediators expressed in the inflammatory site, including immunoreactive substance P (sP), corticotropin-releasing hormone (CRH), and tumor necrosis factor-alpha (TNF alpha). Dexamethasone significantly reduced the volume and cellularity of the inflammatory exudates; in parallel, the levels of immunoreactive sP, CRH, and TNF alpha were significantly suppressed by this glucocorticoid. In contrast, immunoreactive Sms was stimulated by dexamethasone in a time-dependent fashion. These findings suggest another mechanism for suppression of the inflammatory reaction by glucocorticoids via stimulation of local Sms expression, which occurs in parallel to the inhibition of the local inflammatory mediators sP, CRH, and TNF alpha.
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PMID:Somatostatin may participate in the antiinflammatory actions of glucocorticoids. 754 77

Human neutrophils were isolated from blood and aseptic inflammatory exudates. The respiratory burst response was measured as superoxide (O2-) production by a microplate assay system and polarographically as oxygen consumption. Exudate cells exhibited a respiratory burst in response to n-formyl-methionyl-leucyl-phenyl-alanine (FMLP) that was two- to threefold higher than the burst exhibited by peripheral blood cells. The O2- production induced by substance P was also found to be fivefold higher in exudate cells, while the metabolic response to other stimulants such as concanavalin A (con A), phorbol-myristate acetate (PMA), NaF, and immunocomplexes was not primed. Serum-treated zymosan (STZ)-stimulated activity was primed by only 11%. In contrast, superoxide production in response to tumor necrosis factor-alpha (TNF) was decreased in exudate versus blood cells by about 50%. Therefore, the skin-window cells, compared to blood cells, appear to be at the same time primed, unmodified, and desensitized, according to the different stimulants employed.
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PMID:Factor-specific changes in oxidative burst response of human neutrophils in skin-window exudates. 767 71

To test the hypothesis that the cytokines interleukin-6 (IL-6) and IL-8 may play regulatory roles in the aberrant neovascularization in chronic inflammatory diseases, we examined their effects in a rat sponge model and compared their actions with those of IL-1 and tumor necrosis factor-alpha (TNF-alpha). Daily doses of 3 pmol IL-8, IL-1, TNF-alpha, but not IL-6, significantly accelerated the sponge-induced angiogenesis. Although lower doses (0.3 pmol) of these cytokines were inactive, IL-1 acted synergistically with subthreshold daily doses (10 pmol) of substance P (SP) and bradykinin (BK) to produce an intense angiogenic response. In contrast, IL-8 only interacted positively with IL-1, but not TNF-alpha, SP, or BK. There was no synergism or antagonism between IL-6 and SP. These results demonstrate the discrete interactions between angiogenic factors and cytokines in chronic inflammation and suggest that the sponge model is a good means for the study of such interactions.
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PMID:Interleukin-8 stimulates angiogenesis in rats. 768 27

The expression of the alpha 6 beta 4 and alpha 6 beta 1 integrins on epidermal Langerhans cells (LC) before and after mast cell degranulation was studied in cultured human neonatal foreskin by immunohistochemistry. Twenty-four hours after addition of mast cell secretagogues, morphine sulfate, or substance P, solitary mid-epidermal cells showed staining for the integrin subunits alpha 6, beta 4, and beta 1. This expression was not observed in cultured control explants, and immunostained cells were confirmed to be non-epithelial, dendritic cells by immuno-electron microscopy. The identity of these cells as LC was further established by coincident staining for alpha 6 and CD1a using double immunofluorescence labeling. Addition of tumor necrosis factor-alpha (TNF alpha), the predominant cytokine in mast cell granules, also induced LC to express alpha 6 integrins. Furthermore, preincubation of skin organ cultures with anti-TNF alpha antibodies or the mast cell inhibitor cromolyn sodium abrogated the ability to induce alpha 6 integrins on LC consequent to experimental mast cell degranulation by substance P. These data implicate a role for mast cell-derived TNF alpha in the regulation of the integrins alpha 6 beta 4 and alpha 6 beta 1 on LC. These findings may have important implications relevant to mechanisms for spatial localization of LC within the cutaneous compartments during immune responses.
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PMID:Mast cell degranulation upregulates alpha 6 integrins on epidermal Langerhans cells. 834 16

Substance P (SP) is an undecapeptide that has the amino sequence Arg-Pro-Lys-Pro-Gin-Gln-Phe-Phe-Gly-Leu-Met-NH2 and that belongs to a family of structurally related peptides known as tachykinins, the latter are widely distributed in the central nervous system. SP is involved in the biological activities of cells in the immune system, including the induction of cytokines in immune cells. We have investigated the effects of SP on constitutive and/or lipopolysaccharide (LPS)-induced expression of tumor necrosis factor (TNF) in cultured blood monocyte-derived macrophages (MDM). Cells cultured in vitro for 14 days were treated with SP at various concentrations (10(-10) to 10(-6M) in the presence of LPS before culture supernatants were harvested. TNF bioactivity in culture supernatants was measured with L929 cell line MDM from 10 of 12 donors treated with a SP alone showed increased TNF production. SP and LPS also interacted in a synergistic fashion in upregulating TNF production in MDM from responders. The stimulatory effect of SP was inhibited by two SP antagonists, spantide ([D-Arg-1-D-Trp-7-D-Trp-7-D-Trp-9-leu-11]-SP) and CP-96,345 (a nonpeptide antagonist of the SP receptor). In addition, an anti SP polyclonal antibody blocked the SP effect on TNF production in cultured MDM, further indicating the specificity of these effects. These results demonstrate that SP is an important regulator of monokine production by human monocytes/macrophages.
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PMID:Substance P augments tumor necrosis factor release in human monocyte-derived macrophages. 855 79

The present study establishes that tumor necrosis factor-alpha (TNF-alpha) induction of sympathetic substance P (SP) requires sequential induction of both interleukin (IL-1) and leukemia inhibitory factor (LIF). TNF-alpha dose-dependently induces SP, an induction that is secondary to an increase in the SP precursor, preprotachykinin (PPT), mRNA. Since TNF-alpha conditioned medium (CM) mimics the effect of TNF-alpha by raising SP, actions that are not antagonized by a neutralizing TNF-alpha antibody, TNF-alpha induction of SP is mediated by a soluble intermediate or intermediates. The blockade of TNF-alpha action by a specific IL-1 receptor antagonist and the induction of IL-1 mRNA by TNF-alpha suggest that IL-1 is one of the intermediates. Moreover, because immunoprecipitation with LIF antibodies decreases SP-inducing activity of TNF-alpha CM, and because LIF mRNA is also induced by TNF-alpha, LIF is a second intermediate. Furthermore, TNF-alpha-induced LIF mRNA is blocked by the IL-1 receptor antagonist, whereas IL-1-induced LIF mRNA is not affected by TNF-alpha antibodies, suggesting that TNF-alpha first induces IL-1, and IL-1 subsequently induces LIF. These data suggest that TNF-alpha induces SP in sympathetic ganglia through the sequential inductions of IL-1 and LIF.
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PMID:Tumor necrosis factor-alpha induces substance P in sympathetic ganglia through sequential induction of interleukin-1 and leukemia inhibitory factor. 859 5


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