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)

1. Peripheral inflammation is associated with the local production of neuroactive inflammatory cytokines and growth factors. These may contribute to inflammatory pain and hyperalgesia by directly or indirectly altering the function or chemical phenotype of responsive primary sensory neurones. 2. To investigate this, inflammation was produced by the intraplantar injection of complete Freund's adjuvant (CFA) in adult rats. This resulted in a significant elevation in interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) levels in the inflamed tissue and of the peptides, substance P and calcitonin gene-related peptide (CGRP) in the L4 dorsal root ganglion 48 h post CFA injection. 3. The effects of a steroidal (dexamethasone) and a non-steroidal (indomethacin) anti-inflammatory drug on the levels of NGF and IL-1 beta in inflamed tissue were investigated and compared with alterations in behavioural hyperalgesia and neuropeptide expression in sensory neurones. 4. Systemic dexamethasone (120 micrograms kg-1 per day starting the day before the CFA injection) had no effect on the inflammatory hyperalgesia. When the dose was administered 3 times daily, a reduction in mechanical and to a lesser extent thermal sensitivity occurred. Indomethacin at 2 mg kg-1 daily (i.p.) had no effect on the hyperalgesia and a dose of 4 mg kg-1 daily was required to reduce significantly mechanical and thermal hypersensitivity. 5. The increase in NGF produced by the CFA inflammation was prevented by both dexamethasone and indomethacin, but only at the higher dose levels. Dexamethasone at the lower and higher dose regimes diminished the upregulation of IL-1 beta whereas indomethacin had an effect only at the higher dose. 6. The increase in SP and CGRP levels produced by the CFA inflammation was prevented by dexamethasone and indomethacin at the lower and higher dose regimes. 7. Intraplantar injections of IL-1 beta (0.01, 0.1 and 1 ng) produced a brief (6 h) thermal hyperalgesia and an elevation in cutaneous NGF levels which was prevented by pretreatment with human recombinant IL-1 receptor antagonist (IL-1 ra) (0.625 microgram, i.v.). The thermal hyperalgesia but not the NGF elevation produced by intraplantar IL-1 beta (1 ng) was prevented by administration of a polyclonal neutralizing anti-NGF serum. 8. IL-1 ra significantly reduced the mechanical hyperalgesia produced by CFA for 6 h after administration as well as the CFA-induced elevation in NGF levels. Anti-NGF pretreatment substantially reduced CFA-induced mechanical and thermal hyperalgesia without reducing the elevation in IL-1 beta. 9. Intraplantar NGF (0.02, 0.2 and 2 microg) injections produced a short lasting thermal and mechanical hyperalgesia but did not change IL-1beta levels in the hindpaw skin.10. Our results demonstrate that IL-1beta contributes to the upregulation of NGF during inflammation and that NGF has a major role in the production of inflammatory pain hypersensitivity.
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PMID:Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. 758 55

The neuropeptide Substance P (SP) is widely distributed in the peripheral nervous system. Its biologic effects have been extensively studied in the immune system. However, even though the bone marrow (BM) is innervated with SP-immunoreactive fibers and some of its cells not only express SP receptors (T and B cells, endothelial cells, and macrophages) but also produce SP (macrophages, eosinophils, and endothelial cells), the effects of SP on hematopoiesis are scanty. Furthermore, SP induces the production of hematopoietic growth factors (HGFs) (interleukin-1 [IL-1], IL-6, and tumor necrosis factor alpha) from human monocytes. In this study, we have found a potent in vitro stimulatory effect of SP (10(-8) to 10(-12) mol/L) on hematopoiesis for both erythroid and granulocytic progenitors in short-term methyl-cellulose BM cultures. SP alone, in the absence of exogenous HGFs, is able to sustain hematopoiesis in vitro. This stimulatory effect of SP is: (1) mostly mediated by the adherent cells; (2) completely abrogated by two SP receptor (SP-R) antagonists; and (3) partially reduced by anti-IL-1, IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Furthermore, it appears that the stimulatory effect of SP may be mediated by IL-3 and GM-CSF because we have also found that SP induces the release of these two cytokines from BM mononuclear cells. Considering that the SP effect occurs at concentrations as low as 10(-11) mol/L, and via a specific receptor, it appears that SP may play a physiologic role in regulating hematopoiesis, at least partially through the adherent BM cells and the release of HGFs, and may place SP, a neuropeptide, in a new category of hematopoietic regulators.
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PMID:In vitro stimulatory effect of substance P on hematopoiesis. 767 16

Three myelopoietically active, lipopolysaccharide (LPS)-stimulated monokines, interleukin-1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF-alpha), and leukemia inhibitory factor (LIF), were tested for effect in an in vitro model for LPS-induced inflammatory murine monocytopoiesis. Neither cytokine stimulated clonal proliferation of marrow-derived progenitors; however, both IL-1 alpha and TNF-alpha enhanced macrophage colony-stimulating factor (M-CSF)-dependent colony formation. The additional progenitors stimulated by IL-1 alpha and TNF-alpha to form colonies in response to M-CSF were equivalent to the precommitment, transitional progenitors stimulated by M-CSF and bacterial LPS. In addition, the additional colonies elicited by IL-1 alpha and TNF-alpha were not additive in cultures containing both M-CSF and LPS, indicating these colonies arose from the same LPS-responsive, two-signal-dependent transitional progenitors. Leukemia inhibitory factor did not influence M-CSF-stimulated colony formation; however, LIF effected a dose-dependent inhibition of colony formation by transitional progenitors responding to combinations of M-CSF and LPS, IL-1 alpha, TNF-alpha, or an additional transitional cell costimulant, substance P. Neutralizing anti-murine TNF-alpha antibodies abrogated transitional cell colony formation stimulated by combinations of M-CSF and TNF-alpha, IL-1 alpha, LPS, or substance P but had no effect on colony formation stimulated solely by M-CSF. The results indicate that TNF-alpha may be an important positive stimulus for commitment of progenitors to the mononuclear phagocyte lineage and that TNF-alpha may be the endogenous regulator of the costimulatory effects of LPS, IL-1, and substance P. In addition, the results indicate that LIF may play an opposing negative regulatory role acting to inhibit LPS and TNF-alpha stimulation of the transitional progenitors.
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PMID:Opposing effects of tumor necrosis factor alpha and leukemia inhibitory factor in lipopolysaccharide-stimulated myelopoiesis. 767 84

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

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

It has become increasingly clear that immune cytokines perform growth and differentiation functions in the nervous system similar to those performed in the immune system. In previous studies we have shown that interleukin-1 beta (IL-1 beta) raises substance P (SP) and the mRNA coding for its preprotachykinin precursor in cultured sympathetic superior cervical ganglia (SCG) (Jonakait and Schotland, 1990; Hart et al., 1991a). The action of IL-1 is blocked both by depolarization of the ganglia and by glucocorticoid hormones (Hart et al., 1991a). In the present report, we have found that IL-1 does not act directly upon neurons to raise SP, but rather induces the production of a soluble intermediate molecule that raises both SP and the cholinergic-specific enzyme ChAT. Its induction by IL-1 is blocked by the synthetic glucocorticoid hormone dexamethasone; its action is compromised under depolarizing conditions. Because medium conditioned by IL-1 (IL-1CM) is functionally similar to leukemia inhibitory factor (LIF), we sought to determine whether this molecule might be an active constituent of IL-1CM. Immunoprecipitation with an antiserum directed against LIF eliminated large proportions of SP-inducing activity from IL-1CM. In addition, steady-state levels of mRNA coding for LIF are increased by IL-1 treatment of SCG. These data suggest that LIF, induced by IL-1, may ultimately be responsible for the IL-1 induction of SP.
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PMID:Interleukin-1 induces substance P in sympathetic ganglia through the induction of leukemia inhibitory factor (LIF). 768 75

Substance P (SP), a tachykinin neuropeptide, has been previously reported to stimulate IL-2 production in murine T cell lines activated with phorbol esters. Here we extend these observations by establishing the stimulatory effect of SP and related tachykinins on IL-2 production by normal murine lymphocytes and on purified CD4+ T cells. SP proved to be the most efficient IL-2 inducer, exerting its maximal effect at concentrations that were 4 to 5 orders of magnitude lower than the optimal stimulatory concentrations of physalaemin, NKA, or NKB. SP stimulated IL-2 production in a dose-dependent manner, with an optimal concentration range of 10(-10) to 10(-14) M, comparable with physiologic concentrations of SP found in blood and other organs. The effect of SP was carried by the carboxyl-terminal part of the molecule (SP4-11). The specificity of SP activity was confirmed by the inhibitory effect of spantide, a tachykinin antagonist, and of CP-96,345, a nonpeptide antagonist specific for NK-1-type receptors. In unfractionated spleen cell cultures SP induced de novo IL-2 protein synthesis. SP could induce IL-2 production either directly, or in combination with Con A or anti-CD3 antibody treatments. The effect of SP in conjunction with Con A was synergistic, whereas the effect in conjunction with anti-CD3 antibodies was additive, suggesting different molecular mechanisms for these stimulatory factors. In the absence of additional costimuli the effect of SP in unfractionated spleen cell cultures was partially mediated through the induction of IL-1, and both SP and IL-1 were required for IL-2 induction in purified CD4+ T cells. In contrast to its stimulatory effect on the generation of IL-2, SP did not induce IFN-gamma production in murine spleen cells. The stimulatory effect of SP on IL-2 production suggests that some of the already described immunostimulatory activities of SP could be mediated through the up-regulation of IL-2 production in normal lymphocytes.
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PMID:Stimulation of IL-2 production in murine lymphocytes by substance P and related tachykinins. 768 9

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

1. Daily administration of 1 nmol substance P or 3 pmol recombinant human interleukin-1 alpha (IL-1 alpha) caused intense neovascularization in a rat sponge model of angiogenesis. Lower doses of substance P (10 pmol) or IL-1 alpha (0.3 pmol) were ineffective when given alone. When combined at these low doses, substances P and IL-1 alpha interacted to produce an enhanced neovascular response. 2. By use of selective tachykinin NK1, NK2 and NK3 receptor agonists, ([Sar9,Met(O2)11]substance P, [beta-Ala8]neurokinin A(4-10), Succ-[Asp6,MePhe8]substance P(6-11) (senktide), respectively), it was established that the activation of NK1 receptors is most likely to mediate the angiogenic response to substance P in this model. 3. The angiogenic activity of substance P and IL-1 alpha (10 pmol and 0.3 pmol day-1, respectively) was abolished by co-administration of (i) the selective peptide NK1 receptor antagonist, L-668,169 (1 nmol day-1), (ii) the selective non-peptide NK1 receptor antagonists, RP 67580 and (+/-)-CP-96,345 (both at 1 nmol day-1) or (iii) the IL-1 receptor antagonist, IL-1ra, (50 micrograms day-1). In contrast, the selective NK2 receptor antagonist, L-659,874 (1 nmol day-1) was ineffective. 4. The angiogenic action of substance P and IL-1 alpha was resistant to modification by mepyramine (1 nmol day-1) and/or cimetidine (10 nmol day-1), indomethacin (7 nmol day-1) or the platelet-activating factor (PAF) antagonist, WEB-2086 (22 nmol day-1), indicating that histamine, prostaglandins and PAF are not likely to be involved in this neovascular response. 5. The inhibition of the substance P/IL-1 angiogenic response by selective NK1 receptor antagonists or by an IL-1 receptor antagonist demonstrates that angiosuppression can be achieved by blocking the activity of angiogenic factors at the receptor level.
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PMID:Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. 769 87

The neuropeptides are involved in the immune response and in hormonal homeostasis. In this review, we analyse the interactions between the cytokine, the neuropeptide and the hormonal networks in rheumatoid arthritis (RA). We first consider pituitary-adrenal axis dysfunction in RA. An inappropriate response to cortisol in chronic inflammation has been reported, i.e., a decrease of the corticotropin-releasing-hormone (CRH) secretion by the hypothalamus. In contrast, the immunostimulant hormone prolactin (PRL) is upregulated. PRL is released by the pituitary after stimulation by neuropeptides [serotonin, thyroid-releasing-hormone (TRH), or vasoactive-intestinal-peptide (VIP)], and is down-regulated by pro-inflammatory cytokines (IL-1, IL-6). The decreased testosterone concentration observed in male RA patients is associated with HLA B 15. Thus, an altered sex hormone status and a genetic predisposition are related to HLA antigens, and increase the subject's susceptibility to the development of RA. The terminal C fibres release neurotransmitters such as substance P, neurokinin A and calcitonin-gene-related-peptide (CGRP) within the joints, and contribute to local inflammation, synoviocyte proliferation and collagenase production. The parasympathetic system may attenuate the immune response through the neuropeptide VIP. In contrast, the beta 2 adrenergic fibres of the sympathetic nervous system increase joints degradation in RA. This review presents the currently extensive knowledge regarding the immune-neuro-hormonal network, and its implication in the pathogenesis of RA.
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PMID:Modulation of the immune response by the neuro-endocrine axis in rheumatoid arthritis. 795 11


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