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)

Recombinant human interleukin-1 beta (IL-1 beta) significantly increased prostaglandin E2 (PGE2) in a dose-dependent manner in rat astrocyte culture. The minimum effective dose of IL-1 beta was 10(-10)M. IL-1 alpha also increased PGE2, but at a higher concentration. The minimum effective dose of IL-1 alpha was 10(-8)M, indicating it to be 100-fold less effective than IL-1 beta. On the other hand neither IL-1 beta nor IL-1 alpha increased PGE2 production by neuron cultures at any concentration tested. PGE2 response to IL-1 beta was suppressed by simultaneous addition of CRH, somatostatin-14 and LHRH, while these neuropeptides alone did not alter the basal PGE2 levels. Substance P, vasoactive intestinal polypeptide and alpha-MSH altered neither basal nor IL-1 beta-induced increase in PGE2 levels. Angiotensin II (AII) alone also increased PGE2 in cultured astrocytes. Combined addition of AII and IL-1 beta induced a synergistic effect in increasing PGE2 levels. The direct action of IL-1 beta on astrocyte culture suggests that astrocytes may be the target cells for IL-1 beta in the central nervous system. In view of the essential role of central PGE2 in IL-1 beta-induced CRH/ACTH release, these findings suggest the presence of a sophisticated regulatory network in the immune-neuroendocrine interaction.
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PMID:Interleukin-1 beta increases prostaglandin E2 in rat astrocyte cultures: modulatory effect of neuropeptides. 278 13

Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven in part by the deposition of amyloid beta (A beta), a 39- to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Recent descriptions of in vitro neurotoxic effects of A beta support this hypothesis and suggest toxicity might be mediated by A beta-induced neuronal calcium disregulation. In addition, it has been reported that "aging" A beta results in increased toxic potency due to peptide aggregation and formation of a beta-sheet secondary structure. In addition, A beta might also promote neuropathology indirectly by activating immune/inflammatory pathways in affected areas of the brain (e.g., cortex and hippocampus). Here we report that A beta can modulate cytokine secretion [interleukins 6 and 8 (IL-6 and IL-8)] from human astrocytoma cells (U-373 MG). Freshly prepared and aged A beta modestly stimulated IL-6 and IL-8 secretion from U-373 MG cells. However, in the presence of interleukin-1 beta (IL-1 beta), aged, but not fresh, A beta markedly potentiated (3- to 8-fold) cytokine release. In contrast, aged A beta did not potentiate substance P (NK-1)- or histamine (H1)-stimulated cytokine production. Further studies showed that IL-1 beta-induced cytokine release was potentiated by A beta-(25-35), while A beta-(1-16) was inactive. Calcium disregulation may be responsible for the effects of A beta on cytokine production, since the calcium ionophore A23187 similarly potentiated IL-1 beta-induced cytokine secretion and EGTA treatment blocked either A beta or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain regions may be mediated in part by the ability of A beta to exacerbate inflammatory pathways in a conformation-dependent manner.
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PMID:Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. 747 75

Adenylate cyclase was stimulated by prostaglandin E2 (PGE2) and parathyroid hormone-related protein (PTHrP) in both these types of fibroblast and by calcitonin gene-related protein (CGRP) in the human fibroblasts in vitro. PGE2 (1 microM), CGRP (1 microM), and PTHrP (1 microM) stimulated adenylate cyclase up to 50-fold, 10-fold and 9-fold, respectively. Calcitonin (CT), substance P (SP), interleukin-1 beta (IL-1 beta), and transforming growth factor-beta 1 (TGF beta 1) had no effect on adenylate cyclase in either fibroblast. Intracellular Ca2+ (iCa2+) was measured in individual fibroblasts from the periodontal ligament using Indo-1 and an adherent cell analysis and sorting interactive laser cytometer. Ionomycin (3 microM) caused a transient rise of iCa2+ in all human and canine fibroblasts tested. The mean percentage increase in iCa2+ in response to ionomycin was 820 and 840% for human and canine fibroblasts, respectively. The human fibroblasts responded to PGE2 (1 microM) by an increased iCa2+ concentration; the mean percentage increase in iCa2+ was 187%. SP caused a less pronounced increase in iCa2+ in the human fibroblasts (56%). CGRP and SP caused a similar response in the canine fibroblasts. The mean percentage increase in iCa2+ in response to SP and CGRP was 95 and 78%, respectively. PTH, PTHrP, platelet-activating factor, CT, and IL-1 beta had no effect on iCa2+ in either type of fibroblast. The data indicate that cAMP and calcium have roles as intracellular secondary messengers in the action of PGE2, SP, CGRP, and PTHrP in fibroblasts of human and canine periodontal ligament.
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PMID:Effects of hormones and cytokines on stimulation of adenylate cyclase and intracellular calcium concentration in human and canine periodontal-ligament fibroblasts. 750 23

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

Recent evidence suggests that the level of interleukin-6 (IL-6) is elevated in Alzheimer's disease (AD) brains. IL-6 is produced by reactive glial cells and could potentially affect neuronal survival. Understanding the biochemical mechanism that regulates the production and release of IL-6 by astrocytic cells may help to identify potential targets for therapeutic intervention in AD. In the present study, glial fibrillary acidic protein-positive human U373MG astrocytoma cells were used as a model of reactive astrocytes. Production of IL-6 in response to drug treatment was monitored with an ELISA assay. Histamine (1-100 microM), substance P (SP; 1-100 nM), and human interleukin-1 beta (IL-1 beta; 1-30 pM) stimulated the release of IL-6 in a time- and concentration-dependent manner, with EC50 values of 4.5 microM, 8 nM, and 4.5 pM, respectively. The respective effects of histamine, SP, and IL-1 beta were effectively blocked by the histamine H1, SP, and IL-1 receptor antagonists, supporting a receptor-mediated event for these agents. Both histamine and SP enhanced the formation of inositol phosphates and increase intracellular calcium levels, suggesting that the phosphatidylinositol bisphosphate/protein kinase C pathway may be involved in the IL-6 release process. Indeed, phorbol 12-myristate 13-acetate, a protein kinase C activator, also evoked IL-6 release from the U373MG cells. On the other hand, IL-1 beta, which produces a much more robust release of IL-6 than histamine or SP, has no effect on inositol phosphate formation or intracellular calcium levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the release of interleukin-6 from human astrocytoma cells. 751 68

Chronic pain and inflammation increase substance P in sensory fibres of peripheral nerves in which opiate receptors are known to undergo axonal transport. The aim of the present study was to evaluate a possible modulation of axonal transport of opiate receptors in peripheral nerves during inflammation. After intraplantar injection of Freund's adjuvant to rats, the accumulation of mu and kappa opiate receptors increased on both sides of ligature in sciatic nerves of the injected paw. The contralateral side was unaffected and may serve as control. When IL-1 beta was injected into rat paws, the axonal transport of opiate receptors was increased in a similar way. This suggests that IL-1 beta represents a major mediator to sensitize nociceptors during inflammation through a process requiring retrograde signals.
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PMID:IL-1 beta-like Freund's adjuvant enhances axonal transport of opiate receptors in sensory neurons. 752 8

We studied the effects of vasoactive intestinal peptide (VIP) on IgA1 and IgA2 production in human fetal B cells and pre-B cells derived from bone marrow. VIP induced IgA1, IgA2, and IgM production in sIgM+, CD19+ fetal B cells stimulated with anti-CD40 monoclonal antibody (MoAb) without inducing the production of IgG1, IgG2, IgG3, IgG4, or IgE. The anti-CD40 MoAb plus VIP also induced IgA1, IgA2, and IgM production in sIgM-, CD19+ pre-B cells, which was enhanced by the addition of interleukin-7 (IL-7). This induction by VIP was specific, as the anti-CD40 MoAb plus other neuropeptides [ie, somatostatin (SOM) or substance P (SP)] had no effect, and moreover, the induction was specifically blocked by a VIP antagonist. Furthermore, the anti-CD40 MoAb plus various cytokines, including IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, transforming growth factor beta (TGF-beta), low-molecular-weight B-cell growth factor (BCGF), and interferon-gamma (IFN-gamma), did not induce IgA1 and IgA2 production in fetal B cells or pre-B cells. These findings indicate that, in the presence of costimulators, VIP may induce IgA1 and IgA2 production by isotype switching.
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PMID:Induction of IgA1 and IgA2 production in immature human fetal B cells and pre-B cells by vasoactive intestinal peptide. 753 91

Substance P (SP) is a neuropeptide widely distributed in the nervous system. Its release within the bone marrow (BM) can mediate bidirectional neurohematopoietic communication via specific receptors: neurokinin-1R (NK-1R), NK-2R, or NK-3R. We have previously reported that SP effects on hematopoiesis are mediated by an NK-1-type receptor, the BM stroma, and growth factors. Here, we have studied the induction of stem cell factor (SCF) and interleukin-1 (IL-1) by SP in stroma. At 10(-9) mol/L SP, cytokine levels in supernatants were IL-1 alpha, 20 +/- 5 ng/mL; IL-1 beta, 40 +/- 10 ng/mL; and SCF, nondetectable; and the cell-associated levels were SCF, 21 +/- 2 ng/mL; IL-1 alpha, 90 +/- 6 ng/mL; and IL-1 beta, 45 +/- 3 ng/mL. Reverse transcriptase-polymerase chain reaction and ligand-binding studies with stroma stimulated by these two cytokines resulted in (1) NK-1-like receptor mRNA accumulation and (2) downregulation of SP binding sites (day 1) followed by an upregulation (day 3). Low numbers of high-affinity receptors were expressed by day 1 but not by day 3. The results indicate that SP induces IL-1 and SCF in stroma and that these cytokines have the potential to autoregulate NK-R.
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PMID:Substance P (SP) mediates production of stem cell factor and interleukin-1 in bone marrow stroma: potential autoregulatory role for these cytokines in SP receptor expression and induction. 754 64

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

Regulation of substance P receptor (SPR) mRNA was examined in the rat sympathetic superior cervical ganglion (SCG) in vitro and in vivo after axotomy. Interleukin-1 beta (IL-1 beta) treatment of explanted ganglia elevated levels of SPR mRNA. By contrast, dissociated cultures of purified sympathetic neurons, purified fibroblasts, and purified Schwann cells each expressed only low levels of SPR mRNA, and treatment with the cytokine did not alter levels of the receptor mRNA. Treatment of Schwann cell or fibroblast cultures with leukemia inhibitory factor (LIF) also did not alter SPR mRNA. However, treatment of pure neuronal cultures with LIF significantly elevated levels of the receptor mRNA. Further, SPR mRNA increased in pure sympathetic neurons cultured in the presence of conditioned medium from IL-1 beta treated fibroblasts or Schwann cells; this effect was blocked in the presence of LIF antibody. This suggests that the stimulatory effects of IL-1 beta on SPR mRNA in explants is mediated by LIF release. Axotomy of the SCG in vivo resulted in a significant increase in LIF mRNA. Further, axotomy resulted in a significant increase in SPR mRNA, suggesting that LIF may mediate the increase in SPR mRNA. In view of the known effects of substance P (SP) on inflammatory responses, these observations suggest that coordinated expression of SP and SPR mRNA in neurons after nerve injury may participate in inflammatory and repair processes in the ganglion.
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PMID:LIF-and IL-1 beta-mediated increases in substance P receptor mRNA in axotomized, explanted or dissociated sympathetic ganglia. 758 37


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