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)

We performed an open, between patients, placebo controlled study in order to evaluate the effect of the treatment with the non steroidal anti inflammatory drugs indomethacin, diclofenac and naproxen on the concentrations of the cytokines IL-1 beta and IL-6 and of the neuropeptide substance P in plasma and synovial fluid of 24 rheumatoid arthritis patients. All patients had high synovial fluid cytokine and substance P levels, and high plasma cytokine levels at the beginning of the study. The treatment with the non steroidal anti inflammatory drugs significantly decreased both plasma and synovial fluid IL-6 and synovial fluid substance P in comparison to placebo, but did not affect IL-1 beta concentrations. This effect can participate in the therapeutic effect of non steroidal anti inflammatory drugs in rheumatoid arthritis.
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PMID:Plasma and synovial fluid interleukin-1, interleukin-6 and substance P concentrations in rheumatoid arthritis patients: effect of the nonsteroidal anti inflammatory drugs indomethacin, diclofenac and naproxen. 859 83

Substance P (SP), fibroblast growth factor (FGF), and epidermal growth factor (EGF) are mitogens for fibroblasts. EGF acts as a progression factor, whereas FGF and SP have competence factor activity. The ability of eicosanoids to regulate proliferation of fibroblasts and the increased production of prostaglandins by fibroblasts in response to the growth factors, led us to investigate the involvement of cyclooxygenase-dependent arachidonic acid metabolites in the mitogenic response of serum-starved human skin fibroblasts to SP, FGF, and EGF. We tested the interaction of a submaximal concentration of SP(10(-9)M) with baFGF(40 micrograms/ml) and EGF(0.01 microgram/ml) both on fibroblast proliferation and release of arachidonic acid metabolites. A combination of SP and EGF synergistically stimulated fibroblast proliferation and prostaglandin E2 release, whereas addition of SP to FGF-containing cultures did not affect cell growth. Inhibition of cyclooxygenase by acetylsalicylic acid augmented the growth response of fibroblasts to all: SP, FGF, and EGF. In the presence of acetylsalicylic acid, SP combined with FGF enhanced fibroblasts proliferation, whereas a combination with EGF inhibited cellular growth with respect to growth induced by EGF alone. Thus, interactions of SP with FGF and EGF differently affected the mitogenic response depending on the formation of arachidonic acid metabolites. The findings indicate that eicosanoids may be important mediators of competence and progression factor activities that may determine the effects of substance P on fibroblast proliferation in a cytokine network.
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PMID:Interaction of substance P with epidermal growth factor and fibroblast growth factor in cyclooxygenase-dependent proliferation of human skin fibroblasts. 860 Jan 64

Interleukin-1 beta (IL-1 beta) is a cytokine released by activated macrophages and monocytes, which mediates many of the local and systemic responses to inflammation. Interleukin-1 beta induces anorexia in rats when administered peripherally or centrally. An endogenous antagonist for the IL-1 type I receptor has been characterized and cloned (IL-1ra). We have used this protein to ascertain the site of action for the anorexic effects of IL-1 beta. Male rats were food restricted and trained on an operant schedule for food reinforcement. Administration of recombinant human IL-1 beta (4 micrograms i.p. or 40 ng i.c.v.) induced profound decreases in operant responding, with maximal effects 1-4 h post-injection. Interleukin-1ra pretreatment (2.4 mg i.p. or 24 micrograms i.c.v.) completely blocked these effects when administered by the same route. In contrast, i.c.v. Il-1ra only partially blocked the effects of i.p. IL-1 beta, and i.p. IL-1ra was unable to block the effects of i.c.v. IL-1 beta. Interleukin-1ra did not affect responding by itself. These results suggest that IL-1 beta acts as both peripheral and central IL-1 receptors to reduce food motivated behavior. To determine the central site of action of IL-1 beta, small quantities of IL-1 beta (5 and 30 ng) were infused into the ventromedial hypothalamus of male rats. Both doses produced profound decreases in responding; the magnitude and time course of these effects were nearly identical to those observed after i.c.v. administration. These results suggest that the VMH may serve as a central site of action for the depressive effects of IL-1 beta on food intake. There is much controversy over the pathways of communication from the immune system to the brain. To test the hypothesis that the peripheral immune stimulus is transmitted to the brain via a neutral communication pathway, mice were injected with lipopolysaccharide at a behaviorally active dose (10 micrograms i.p.). This treatment increased the concentrations of substance P, neurokinin A, and calcitonin gene-related peptide in mouse spinal cord in a prostaglandin-dependent manner. Maximal increases in neuropeptide content were observed 1 h post-injection. Finally, subdiaphragmatic vagotomy was found to attenuate the reduction in food-motivated behavior induced by both IL-1 beta and lipopolysaccharide in mice.
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PMID:Mechanisms of sickness-induced decreases in food-motivated behavior. 862 24

Substance P (SP) is a neuropeptide which has been reported to have immunomodulatory activity. Most studies on SP have been performed on cells of the peripheral immune system. More recently, SP has been reported to have stimulatory activity on human bone marrow cells in vitro, and this activity was dependent on the presence of an adherent layer of cells. The in vitro adherent layer represents the stromal cells of the marrow. In this study, we directly addressed the effect of SP on cultured bone marrow stromal cells. Since stromal cells play an important role in the regulation of hematopoiesis, interactions of neuropeptides such as SP with this cell population could lead to an alteration of stem cell development within the bone marrow. Previously we have shown that SP stimulates protein synthesis in this cell population with two waves of protein synthesis activation, after 2 hr and 48 hr of SP incubation. In this study, we asked whether levels of known stromal cell cytokines were altered in response to SP incubation. We assayed the levels of Interleukin-7 (IL-7) and Stem Cell Factor (SCF) associated with the stromal cell surface following 2 hr and 48 hr of SP incubation. Cells were stimulated with SP for 2 hr or 48 hr. Following SP incubation, cells were washed and the levels of cell associated cytokine was determined by ELISA. Following 2 hr of treatment, 0.1 nM of SP significantly increased (p = 0.05) the level of IL-7 as compared to untreated controls. After 48 hr of treatment, 1, 10, and 100 nM SP significantly increased the levels of IL-7 in this cell population. When SCF levels were assayed, SP at all concentrations tested was found to increase significantly the levels of SCF following 2 hr of incubation. Following 48 hr of incubation, 10 and 100 nM of SP significantly increased the levels of SCF. The ability of SP to affect cytokine levels varied with time. Following 2 hr of SP incubation, cytokine levels were enhanced at the lower end of the concentration range as compared to 48 hr of SP treatment. A 48 hr incubation with SP yielded the highest levels of cytokine at the higher end of the concentration range. Taken together, the results of these studies suggest that SP has an immunoregulatory effect on bone marrow stromal cells leading to alteration in the production and/or secretion of regulatory cytokines such as IL-7 and SCF.
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PMID:Substance P mediated stimulation of cytokine levels in cultured murine bone marrow stromal cells. 864 13

Substance P (SP) can produce cytokine-like responses by astrocytes and mononuclear cells. In an effort to identify neurokinin-1-receptors (NK1-R), an antibody to NK1-R was generated by using a linear peptide sequence from the deduced third extracellular region (ECR) corresponding to the seven transmembrane rat brain NK1-R. The ECR-3 peptide was coupled to keyhole-limpet hemocyanin and the antisera produced in rabbits was purified by binding to a peptide-affinity matrix. The specificity for the anti-peptide antibody was shown by its reactivity to the ECR-3 peptide by ELISA. The anti-ECR-3 peptide antibody could detect, by Western blot analysis of SDS-PAGE-separated rat brain membranes, a single band with an apparent molecular weight (MW) of 53-54 kDa. An affinity matrix made from the anti-ECR-3 antibody was used to isolate NK1-R from rat brain membranes which exhibited two products on SDS-PAGE with apparent MW of 54 and 44 kDa. The C6 astrocytes were shown to express NK1-R as determined by [125I]Bolten-Hunter SP binding to intact cells with a Kd = 0.32 nM. These C6 cells did not co-express either NK2-R or NK3-R when analyzed at the mRNA level. The anti-ECR-3 peptide antibody could inhibit [125I]Bolten-Hunter SP binding to intact C6 astrocytes and CHO cells expressing NK1-R by greater than 95% when compared to normal rabbit IgG which failed to inhibit radiolabeled SP binding. Thus, an antibody which recognizes surface determinants to the NK1-R could be generated upon immunization with an NK1-R peptide.
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PMID:Recognition of neurokinin 1 receptor (NK1-R): an antibody to a peptide sequence from the third extracellular region binds to brain NK1-R. 870 30

Recent studies have suggested that substance P (SP) and some other neuropeptides are able to induce the synthesis of the proinflammatory cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6) in peripheral blood mononuclear cells. In the present study, we re-examined these findings by using a completely endotoxin-free monocyte cultivation system. We demonstrate that the neuropeptides SP, vasoactive intestinal peptide, substance K. cholecytokinine, alpha-endorphin and beta-endorphin are consistently unable to induce the synthesis of IL-1 and IL-6 in human peripheral blood monocytes. However, low amounts of LPS (1 pg/ml) synergized with SP to induce IL-6 mRNA expression. In contrast to its lack of effect in monocytes, we were able to confirm the ability of SP to induce cytokine synthesis in astrocytic cells. Our results raise questions about previous results claiming a neuropeptide-induced synthesis of proinflammatory cytokines in human monocytes. In conjunction with other studies, we suggest that undetected levels of endotoxin/LPS in the culture medium may have been primarily responsible for results suggesting an inductive effect of neuropeptides on cytokine synthesis in monocytes.
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PMID:Effects of substance P and selected other neuropeptides on the synthesis of interleukin-1 beta and interleukin-6 in human monocytes: a re-examination. 876 29

The role of somatostatin (SRIF) in controlling the granulomatous inflammatory response to infection with the parasite Schistosoma mansoni was explored in mice. The murine granulomas contain SRIF-14. Immunoreactive SRIF and prepro SRIF localize in the cytoplasmic granules of macrophages within the granulomas. The granulomas contain mRNA for prepro SRIF and are not innervated. The production of SRIF by the inflammatory cells appears to be inducible. The granulomas contain mRNA for the SRIF receptors sst2A and sst2B, which are expressed mainly on CD4- T lymphocytes and bind SRIF-14 with high affinity. Antigens from the schistosome eggs stimulate granuloma T lymphocytes to produce cytokines. Interferon-gamma (IFN-gamma) is one such cytokine made by CD4+ T lymphocytes. SRIF-14 suppresses antigen-induced IFN-gamma production from granuloma cells, and this effect is blocked by anti-sst2 antibody. SRIF was shown to inhibit IFN-gamma-induced immunoglobulin G2a (lgG2a) synthesis in murine schistosomiasis. SRIF also blocks substance P (SP)-stimulated IFN-gamma and lgG2a secretion. Schistosome-infected animals treated with the SRIF analog octreotide form smaller granulomas that secrete substantially less IFN-gamma and lgG2a. Unpublished observations suggest that SRIF does not modulate schistosome egg antigen- or concanavalin A-stimulated granuloma lymphocyte proliferation in murine schistosomiasis. In conclusion, SRIF may be an important factor in the control of the granulomatous inflammatory response in murine schistosomiasis.
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PMID:Granulomas in murine schistosomiasis mansoni have a somatostatin immunoregulatory circuit. 876 93

The first week of dietary magnesium deficiency in rodent models is characterized by the induction of raised levels of neuropeptides (substance P [SP] and calcitonin gene related peptide [CGRP]), followed shortly thereafter by inflammatory cytokine release. Since neuropeptides participate in neurogenic inflammation, we have proposed that the neurogenic inflammatory response plays a role in the pathology of magnesium deficiency. However, the association between the early neuropeptide release and the subsequent pathology in this model remains unclear. Peripheral blood T lymphocytes were obtained from Balb/c mice fed a magnesium-deficient diet (approximately 1.8 mmol Mg/kg), or the same diet supplemented with 20 mmol MgO/kg. These cells were incubated in medium containing 10(-10) to 10(-5) M SP, after which the cells were examined for expression of SP receptors and the supernatants were collected and examined by immunochemical techniques for the presence of T lymphocyte associated cytokines. SP stimulation induced the secretion of interleukin (IL)-2, 4, 5, 10, 12, 13 and interferon-gamma (IFN-gamma). T lymphocytes from magnesium-deficient animals, when compared to magnesium-sufficient ones, secreted increased levels of these cytokines. The secretion of these cytokines was maximal at either 5 days (IL-4, IL-5) or 7 days (II-2, IL-10, and IFN-gamma) of magnesium deficiency. This increased sensitivity to SP appears to be related to an increased expression of SP receptors on the surface of T lymphocytes during the first week of magnesium deficiency. These data indicate that SP released early during magnesium deficiency exerts a regulatory role on T lymphocyte cytokine production, especially those cytokines regulating mast cell and immune responses leading to the onset of an immunopathological state.
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PMID:Immunoregulation by neuropeptides in magnesium deficiency: ex vivo effect of enhanced substance P production on circulating T lymphocytes from magnesium-deficient mice. 881 89

The epithelium of the gastrointestinal tract is continuously exposed to the external environment containing food antigens, microbes and other pathogens. Immunologic and nonimmunologic mechanisms contribute to the neutralization and elimination of these foreign antigens. The immune system of the intestine is the most extensive in the organism and involves diffuse populations of immune cells, lymphoid aggregates and intraepithelial lymphocytes. On the other hand, the functions of the digestive tract contribute to the overall host defense (mucus secretion, gastric acid secretion, water and electrolyte secretion and peristaltism). These functions are regulated by intrinsic and extrinsic nervous systems. It is currently recognized that the physiological and pathological responses of the intestine require an integrate neuroimmune network. Such neuroimmune regulation is based on anatomical and biochemical supports. Indeed, there are membrane-to-membrane contacts between axonal varicosities and the immune cells. Specific receptors for neurotransmitters such as substance P, vasoactive intestinal polypeptide and somatostatin have been identified in many immune cells. Nerve profile change has been described under pathological conditions such as parasitic infections and acute phase of inflammation. In addition to supporting the growth and survival of several populations of nerves the classical nerve growth factor (NGF) has been shown to affect an immune cell population by inducing mast cell hyperplasia. Furthermore the NGF can induce mast cell degranulation, acting directly on mast cell membrane NGF receptors or indirectly by NGF-mediated release of substance P by peripheral extrinsic or intrinsic nerves. Moreover, non-immune cells such as epithelial and smooth muscle cells can produce immunologic messengers under pathological conditions such as infectious diseases or inflammation. Besides the local regulation of gut functions, neuroimmune control can be exerted at extra-intestinal sites. During physiological and pathological conditions, gastrointestinal secretions and motor events are strongly regulated by the central nervous system. Moreover, infectious agents can induce cytokine and particularly interleukin-1 release by the brain astrocytes and microglial cells which have been shown to play a pivotal role in fever induction and modifications of the gastrointestinal functions. Visceral afferent fibers play a pivotal role in 'cross-communication' between central sites and immune response. Recent studies evoke, more specifically, the role of vagus as a key modulatory participant in the close relationship between the extraintestinal nerves and the immune system. Future work in this field will clarify the role of the different participants in the intimate communication between the gastrointestinal tract, immune system and central nervous system.
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PMID:Integrative neuroimmunology of the digestive tract. 882 13

Using mouse peritoneal cavity mast cells, we investigated the effects of FK506 and cyclosporin A (CsA) on cell proliferation and histamine release induced by anti-IgE antibody, calcium ionophore (A23 187), or neuropeptide (substance P). Both FK506 and CsA inhibited cytokine-dependent mast cell proliferation in a dose-dependent manner. The inhibitory effects of these compounds on mast cell proliferation was reversible; the removal of the chemicals from the incubation medium resulted in the reinitiation of mast cell proliferation. Flow cytometric analysis suggested that the inhibitory effect of FK506 and CsA was mostly due to G1/S boundary block, although a significant number of G2-arrested cells were also observed following FK506 treatment. Both FK506- and CsA-treated mast cells showed a similar inhibition of histamine release induced by A23187. However, CsA at higher concentrations inhibited the histamine release induced by anti-IgE antibody or substance P more markedly than FK506. Cellular histamine content was decreased by CsA treatment while FK506 had no effect. The staining properties of peritoneal mast cells changed from connective tissue-type mast cell-like to mucosal mast cell-like during CsA treatment but not during FK506 treatment. Thus FK506 and CsA have different effects on mast cell proliferation as well as histamine release, that might be associated with a phenotypic change of the cells during culture.
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PMID:Effects of FK506 and cyclosporin A on proliferation, histamine release and phenotype of murine mast cells. 884 28


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