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)

Autonomic neurons help to regulate immune responses, and there are reciprocal interactions between the nervous and immune systems. This study seeks to define some of the molecular mechanisms that may underlie such interactions. Immunoblot analysis indicated that cultured sympathetic neurons synthesize and release the cytokine interleukin 1 beta (IL-1 beta). In addition, RNA blot analysis of cultured sympathetic neurons demonstrated that the neurons contain mRNA encoding IL-1 beta. It was previously shown that explant cultures of sympathetic ganglia and dissociated cocultures of neurons with ganglionic nonneuronal cells synthesize substance P, whereas in situ levels of substance P and its mRNA are low. An antagonist at the interleukin 1 receptor markedly depressed this increase in substance P in cultures, suggesting that endogenous IL-1 beta mediates the synthetic response, at least in part. Because pure neuronal cultures do not contain substance P and neurons synthesize and release IL-1 beta, the actions of the cytokine require the presence of ganglion nonneuronal cells. These observations suggest a role for autonomic neurons in influencing immune responses by synthesizing and secreting at least two known immunoregulators, the cytokine IL-1 beta and the neuropeptide substance P.
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PMID:Cultured sympathetic neurons synthesize and release the cytokine interleukin 1 beta. 127 79

Interleukin-1 receptor antagonist (IRA) is a secretory product of human monocytes or related cell lines that acts as a pure interleukin-1 (IL-1) antagonist in several bioassays. IRA administration was reportedly a life-saving intervention in rabbits injected with lethal doses of bacterial lipopolysaccharide (LPS). We report the inhibitory effect of IRA on three distinct types of vascular responses to IL-1 in rabbit isolated blood vessels. The rabbit isolated superior mesenteric artery, when precontracted with phenylephrine, relaxed in a sustained manner in less than 30 min following application of recombinant interleukin-1 beta (12-290 pM), and this was a prostaglandin (PG)-dependent and endothelium-independent process. IRA (human recombinant sequence; 0.9-15 nM) behaved as an antagonist of IL-1 alpha or IL-1 beta, based on the surmountability and the concentration dependence, but could only prevent the effect of IL-1, not reverse it. IRA had no direct effect on the preparation and did not influence the acute relaxing effect elicited by substance P or iloprost, a PGI2 mimetic. Exposure to IL-1 beta depressed the response to noradrenaline (NA) in several hours in rabbit aorta rings. The inhibitory effect of IL-1 beta was endothelium and prostaglandin independent, but was prevented by a treatment with NG-nitro-L-arginine (a nitric oxide synthesis inhibitor), cycloheximide, dexamethasone, or IRA. Using the residual NA-induced contraction as a quantification of the IL-1 agonist effect, IRA was a very potent antagonist of IL-1 beta but was not totally surmountable.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of interleukin-1 receptor antagonist on three types of responses to interleukin-1 in rabbit isolated blood vessels. 138 81

The thymic repertoire of neuroendocrine 'self' antigens has been previously described on the basis of the intrathymic expression of neurohypophysial (NHP)- and tachykinin-related peptide signals and receptors. According to that model, the cryptocrine signalling between thymic epithelial/nurse cells and thymocytes through NHP-related signals and receptors constitutes one accessory pathway in the process of T-cell differentiation and/or activation. A pharmacological manipulation of that novel type of cell-to-cell signalling was tested by the investigation of the immunomodulatory properties of novel cyclic hexapeptide oxytocin (OT) antagonists (MSD Research Laboratories). These compounds were found to significantly inhibit the productions of cytokines (mainly IL-1 beta and IL-6) elicited by anti-CD3 treatment of human whole blood cell cultures. Cytokine productions were more significantly reduced by OT antagonists in whole blood cell cultures derived from female volunteers than in those obtained from male donors, suggesting an influence of the gonadal steroid environment on the expression of NHP peptide receptors by immune cells. These observations support the concept of novel immunomodulating approaches through immune-specific neuropeptide antagonists, as well as the pharmacological value of such strategies in selective immunotherapy.
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PMID:Immunomodulatory properties of cyclic hexapeptide oxytocin antagonists. 149 61

The nervous and immune systems interact in a bidirectional fashion. For example, the neuropeptide substance P (SP) has been implicated in a variety of immune responses. Conversely, cytokines, a class of immunoregulatory glycoproteins, affect the synthesis of neurotransmitters and neurotrophic factors. This paper examines the role of cytokines in regulating neuropeptide expression in sympathetic neurons. Exposure of cultured explants of the rat superior cervical ganglion to the cytokine interleukin 1 beta (IL-1 beta) increased levels of SP. IL-1 beta increased neuronal SP expression in dissociated cultures of ganglion neuronal and nonneuronal cells but had no effect on peptide content in pure neuronal cultures. By contrast, treatment with a differentiation-promoting protein, leukemia inhibitory factor, increased SP in both pure neuronal and mixed cultures, indicating a different mechanism of action for the two molecules. The specificity of the IL-1 beta effect was further demonstrated by the lack of response to treatment with other cytokines, including interleukin 2, interleukin 6, and tumor necrosis factor alpha. The cell type necessary for the IL-1 beta activity is probably the ganglion Schwann cell. Treatment with a synthetic immunosuppressant glucocorticoid, dexamethasone, blocked the increase in SP after treatment with IL-1 beta. These observations support the hypothesis that neuropeptide expression is regulated, in part, by interactions with specific immunoregulators. In addition, the data suggest a role for SP in mediating the response of the superior cervical ganglion to injury of the ganglion itself or to the fibers innervating it.
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PMID:Cytokine regulation of substance P expression in sympathetic neurons. 170 35

Substance P (SP) is an undecapeptide with neurotransmitter and immunoregulatory properties. In murine schistosomiasis, ova naturally induce liver and intestinal granulomas. These granulomas contain macrophages, and eosinophils that produce SP. A report showed that human blood monocytes isolated by adherence release interleukin-1 (IL-1) in response to SP (Lotz et al. (1989) Science 241, 1218). IL-1 is important for initiation of hypersensitivity granulomas. Therefore, it was determined whether SP modulates granuloma macrophage IL-1 production in murine schistosomiasis. Macrophages were obtained from lung and liver granulomas, and from spleens of infected mice. A thymocyte proliferation assay measured IL-1 activity in culture supernatants. Total RNA, extracted from macrophages, was assayed for IL-1 alpha and beta mRNA by Northern blotting using cDNA probes. In response to lipopolysaccharide (LPS), splenic macrophages and macrophages from young lung granulomas released appreciable IL-1. Macrophages from liver granulomas, that were lesions older than the lung granulomas, were unresponsive to LPS with regard to IL-1 secretion. Yet, granuloma macrophages spontaneously expressed IL-1 alpha and beta mRNA. LPS enhanced IL-1 mRNA expression in both splenic and granuloma macrophages. Exposure of macrophages from all sources to SP did not alter IL-1 secretion or gene expression. Similarly, the responsiveness of macrophages to LPS was not affected by concomitant exposure to SP. It is concluded that, in the murine system, SP does not directly influence splenic or granuloma macrophage IL-1 secretion or gene expression. Also, it appears that macrophage secretion of IL-1 is rapidly down-regulated following granuloma elicitation.
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PMID:Substance P does not alter interleukin-1 expression by splenic or granuloma macrophages in murine schistosomiasis. 171 19

We have previously shown that neutral endopeptidase (NEP; EC 3.4.24.11) regulates neuropeptide-induced responses. Recently, Pierart et al. reported that NEP degraded purified interleukin-1 (IL-1) using thymocyte proliferation assay. Since IL-1 is an important cytokine in the immune response and inflammation, we have assessed whether NEP hydrolyzes recombinant human IL-1 beta using three assay systems (bioassay, immunoassay, and HPLC analysis). NEP on the NALM-6 cells (both intact cells and the solubilized plasma membrane fraction) efficiently hydrolyzed Met5-enkephalin and substance P. However, NEP did not significantly decrease the amount of rhIL-1 beta assessed by the growth inhibitory activity of a human melanoma, by the immunoassay, or by the direct analysis on HPLC. Therefore, we conclude that NEP does not significantly hydrolyze rhIL-1 beta. Our results suggest that, in contrast to the regulatory role of NEP in neuropeptide-induced responses, NEP is not a regulatory enzyme for IL-1-induced responses.
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PMID:Neutral endopeptidase (EC 3.4.24.11) does not hydrolyze recombinant human interleukin-1 beta. 171 45

We have investigated the effects of interleukin-1 beta (IL-1 beta) on the induction of substance P (SP) in cultured sympathetic ganglia. Northern blot analysis reveals that SP increases are secondary to an increase in mRNA coding for the preprotachykinin (PPT) precursor of SP. Nuclear transcription assays detect an early increase in PPT-specific nascent transcripts, suggesting that the ultimate effect of IL-1 is on transcription itself. Depolarizing agents, interferon-gamma, glucocorticoid hormones, and prostaglandin synthesis inhibitors all diminish the induction of SP and PPT mRNA by IL-1. Since SP has stimulatory effects on the immune system, the IL-1-induced increase in ganglionic SP may be one means by which the nervous and immune systems interact during an acute response to ganglionic injury.
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PMID:Substance P gene expression is regulated by interleukin-1 in cultured sympathetic ganglia. 171 2

Conditions were established to stimulate human gingival fibroblast explant cultures to synthesize milligram quantities of the metalloproteinase proenzymes, prostromelysin and procollagenase. To stimulate enzyme production, cells were treated with 1 nM recombinant human IL-1 beta for approximately 7 days under serum free conditions. Using a combination of rapid column chromatography steps, approximately 10 milligrams of prostromelysin and 5 milligrams of procollagenase were purified from 1 liter of conditioned media. Prostromelysin electrophoresed as a doublet with molecular weights of 55,57 kD, whereas, procollagenase migrated with slightly lower molecular weights of 52, 54 kD. Both proenzymes were treated with trypsin or aminophenylmercuric acetate to generate active species. The molecular weights of the active enzymes were approximately 10 kD smaller than the proenzymes. Active enzymes were inhibited by metal chelators and the natural metalloproteinase inhibitor, tissue inhibitor of metalloproteinase (TIMP), but not by the serine protease inhibitor, phenylmethylsulfonyl fluoride (PMSF). Activated stromelysin degraded a number of substrates including transferrin, proteoglycan monomer, proteoglycan aggregated with hyaluronic acid, and substance P. By contrast, collagenase degraded interstitial type I collagen and the peptide thioester, Ac-Pro-Leu-Gly-SCH(iBu)Co-Leu-GlyOEt. Identity of both enzymes were confirmed by amino-terminal protein sequence analysis as well as by immunoblot analysis using monoclonal antibodies.
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PMID:Production and purification of prostromelysin and procollagenase from IL-1 beta-stimulated human gingival fibroblasts. 217 90

A duodenal biopsy culture technique was used to investigate the effect of substance P on lymphokine secretion by the human gut associated lymphoid tissue. Duodenal biopsies of 7 healthy volunteers were cultured in 1 ml medium each with Pokeweed mitogen (1 microgram/ml) for 4 days at 37 degrees C. Substance P (SP) was added in concentrations ranging from 10(-12) M to 10(-6) M. Media were changed every day. Interleukin (IL)-1 beta, IL-2 and IL-2-receptor activities were determined by means of specific ELISAs. Values were referred to 5 mg biopsy weight and expressed as per cent change of basal Pokeweed mitogen-pulsed supernatant activities. 10(-8) M and 10(-6) M SP led to a decrease of IL-1 beta activity (78 +/- 13.9% and 62.8 +/- 17.1%, respectively, alpha = 0.01 each). In contrast, 10(-8) and 10(-10) M SP showed an increase in IL-2 activity up to 182.9 +/- 94.5% and 295.6 +/- 144.7%, respectively. 10(-6) M and 10(-8) M SP enhanced IL-2 receptor activities by 81.5 +/- 70% and 40.9 +/- 11.8%, respectively (alpha = 0.05). The present data demonstrate for the first time distinct SP-mediated effects on lymphokine activities in supernatants of cultured human duodenal biopsies.
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PMID:Substance P modulates lymphokine activities in supernatants of cultured human duodenal biopsies. 246 74

Kinins are vasoactive peptides whose potent inflammatory and bone resorbing properties suggest a role for these autacoids in the pathogenesis of inflammatory arthritis. We used cultured human synovial cells as a model to evaluate the effects of bradykinin on articular tissue. In resting synovial cells, bradykinin was a relatively ineffective stimulus for PGE2 production. However, after a period of preincubation with the cytokine, IL-1, which is itself a stimulus for PGE2 production, synovial cells exhibited a further striking time- and dose-dependent response to bradykinin. Maximal release of PGE2 was observed in response to 10(-7) to 10(-6) M bradykinin after first pretreating the cells for 24 h with 5 to 10 U/ml of IL-1. rIL-1 alpha and IL-1 beta, as well as rTNF-alpha, induced a similar response to bradykinin in synovial cells, whereas recombinant IL-2 did not. The bradykinin analog, lysylbradykinin, was equipotent in inducing PGE2 release from IL-1 pretreated synovial cells, whereas des(Arg9) bradykinin, substance P, and neurokinins A and B were ineffective in this regard in both IL-1-pretreated and in resting cells. Synovial cells derived from patients with rheumatoid arthritis and osteoarthritis responded similarly to bradykinin. The synergistic response in PGE2 production induced by IL-1 and bradykinin was significantly inhibited by pretreatment with 1 microM indomethacin or dexamethasone (96 and 94% inhibition, respectively). In addition, the response was abrogated by pretreatment with 10 micrograms/ml of cycloheximide or actinomycin D (81 and 97% inhibition, respectively). These data provide the first description of synergism of IL-1 with a noncytokine peptide in human synovial cells. The ability of IL-1 to increase the responsiveness of synovial tissues to bradykinin may play an important role in potentiating inflammatory responses within the joint.
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PMID:Preincubation of human synovial cells with IL-1 modulates prostaglandin E2 release in response to bradykinin. 247 45


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