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)

Dietary deficiency of magnesium (Mg) in rodents results in cardiomyopathic lesion formation. In our rat model, these lesions develop after 3 weeks on the Mg-deficient diet; significant elevation of several cytokines, IL-1, IL-6 and TNF alpha also occurs. In probing the mechanisms of lesion formation, we obtained data supporting the participation of free radicals (Freedman AM et al.: Bioch Biophys Res Commun 1990; 170: 1102). Recently, we identified an early elevation of circulating substance P and proposed a role of neurogenic peptides during Mg-deficiency (Weglicki WB, Phillips TM: AM J Phys 1992;262:R734). The present study was designed to evaluate the contribution of neurogenic peptides to the pathogenesis of Mg-deficiency. In the blood, substance-P and calcitonin gene related peptide (CGRP) are elevated during the first week on the diet. During the second week, circulating histamine, PGE2 and TBAR-materials were elevated and red cell glutathione was reduced, all prior to the elevation of the inflammatory cytokines during the third week. When the rats were treated with the substance P-receptor blocker [CP-96,345], the levels of substance P and CGRP remained elevated; however, increases in histamine, PGE2, TBAR-materials, and the decrease in red cell glutathione were inhibited; also, the development of cardiac lesions was inhibited significantly. These data support a central role for neurogenic peptides, especially substance P, in the development of cardiomyopathic lesions during Mg-deficiency.
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PMID:Neurogenic peptides and the cardiomyopathy of magnesium-deficiency: effects of substance P-receptor inhibition. 802 89

Light chain gene rearrangement during mammalian pre-B differentiation generally occurs in an orderly manner, beginning with kappa genes and proceeding through lambda genes. We have previously shown that human pre-B cell differentiation in vitro leads to a skewing toward lambda expression, resulting in a higher percentage of lambda+ cells than kappa+ cells. We now report that the multifunctional polypeptide transforming growth factor-beta (TGF-beta) exerts a selective inhibitory effect on the acquisition of cell surface lambda light chains during in vitro differentiation of normal human pre-B cells, giving rise to a balanced ratio (approximately 1:1) of kappa+ to lambda+ cells that resembles what normally exists in vivo. The TGF-beta effect was ablated using a neutralizing anti-TGF-beta antiserum and TGF-beta had no significant effect on the acquisition of kappa or surrogate light chains. Experiments using highly enriched pre-B cells (90-95% cytoplasmic mu+) suggested that the TGF-beta effect was directly on the pre-B cell or the pre-B cell to mu+/lambda+ immature B cell transition. The following peptides, cytokines, and antibodies had no effect on light chain acquisition or expression: substance P, vasoactive intestinal peptide, leu/met enkephalin, IL-1, IL-4, IL-7, anti-class II MHC, anti-CD24, anti-CD40, and the CD10 inhibitor phosphoramidon. A selective regulatory role for TGF-beta on normal human B cell development in the bone marrow microenvironment is suggested by these results.
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PMID:Transforming growth factor-beta regulates normal human pre-B cell differentiation. 815 4

Phospholipase C-mediated release of inositol trisphosphate, followed by an increase in free intracellular calcium, is an important signal transduction pathway for several membrane receptors. In the present investigation, the coupling of various receptors to phospholipase C was studied in the human keratinocyte line HaCaT. Inositol trisphosphate formation was determined by anion-exchange chromatography, and the release of intracellular calcium was analysed with the fluorescence probe Fura-2 AM. Activation of HaCaT keratinocytes with bradykinin resulted in a time- and dose-dependent release of inositol trisphosphate and intracellular calcium, with an EC50 value of 50 nM for bradykinin-induced inositol trisphosphate formation. The mediators and cytokines IL-1, IL-4, IL-6, IL-8, EGF and TGF alpha, as well as bombesin, prolactin, carbachol, substance P and retinoic acid, did not activate this pathway. The inability of the mediators examined to activate phospholipase C may be due to lack of the respective cognate receptors or to the use of other signal transduction pathways.
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PMID:Inositol phosphate formation and release of intracellular free calcium by bradykinin in HaCaT keratinocytes. 830 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

Local application of the bradykinin B1 receptor antagonist desArg9[Leu8]BK, but not the B2 receptor antagonist Hoe 140, attenuated by approximately 50% the polymorphonuclear leukocyte accumulation into 6-day-old air pouches observed in response to application of murine IL-1 beta (5 ng). The selective appearance of a chemotactic response to the bradykinin B1 receptor agonist desArg9BK only in air pouches pretreated (4 h) with IL-1 beta indicated the involvement of this receptor type during this acute inflammation model. The pro-migratory action of desArg9BK was magnified when the effect of IL-1 on polymorphonuclear leukocyte accumulation had subsided (i.e., 24 h post-IL-1). desArg9[Leu8]BK, but not Hoe 140, antagonized the effect of desArg9BK, indicating an action on B1 receptors, but not B2 receptors. The cellular infiltration observed following application of desArg9BK in IL-1-sensitized air pouches was due to the release of neuropeptides from C fibers, as indicated by the inhibitory action of the substance P antagonist, RP 67,580, and the calcitonin-gene related peptide antagonist, CGRP-(8-37). In conclusion, this study provides evidence that activation of C fibers, which is necessary for the achievement of a full chemotactic action of IL-1, is due to up-regulation (or induction) of bradykinin B1 receptors and describes, for the first time, a relationship between these receptors and polymorphonuclear leukocyte recruitment.
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PMID:Involvement of bradykinin B1 receptors in the polymorphonuclear leukocyte accumulation induced by IL-1 beta in vivo in the mouse. 859 72

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

The ability of the cellular components of the skin immune system to mount various types of immune responses is largely dependent upon their ability to release and to respond to different signals provided by immunoregulatory mediators such as cytokines and neuropeptides. In principle, almost every cytokine known so far, including interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), colony stimulating factors (CSF) and several growth factors can be detected in the skin under certain physiological or pathological conditions. There is recent evidence that neuropeptides such as substance P, calcitonin-related gene product (CGRP) a.o. as well as neurohormones such as proopiomelanocortin (POMC), which is the precursor of several peptidehormones including melanocyte stimulating hormones (MSH), are present in epidermal cells, cutaneous tumors and inflammatory cells infiltrating the skin. In addition to their well known functions as neurotransmitters or hormones, these peptides have recently been recognized as potent immunomodulating agents which inhibit the production and activity of immunoregulatory and proinflammatory cytokines (IL-1, IL-2, IFN gamma) but induce the release of factors, e.g., IL-10, which downregulate immune responses. Accordingly, in animals, alpha MSH and CGRP have been shown to inhibit the induction of contact hypersensitivity reactions. Therefore, a complex network of interacting mediators including cytokines and neuropeptides within the cutaneous microenvironment are crucial elements of the induction, elicitation and regulation of cutaneous immune responses.
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PMID:Regulation of the immune response by epidermal cytokines and neurohormones. 890 47

Substance P (SP) released by cutaneous C fibres is involved in the physiopathology of cutaneous lesions. As normal human keratinocytes have been reported to express SP receptors, we studied the effects of SP on keratinocyte activation markers such as ICAM-1 induction and cytokine production. Human keratinocytes derived from skin obtained during plastic surgery were cultured in defined medium (MCDB 153) and were stimulated by SP. Flow cytometry analysis showed that SP (10(-7) and 10(-5) M) as well as the specific NK1 agonist Sar9Met(O2)11SP (Sar Met) induced a slight but significant expression of ICAM-1 at the cell surface during treatment periods of 24 h and 48 h. SP (10(-5) M) also induced a significant but transient increase in the production of IL-1alpha, IL-1beta, IL-1 receptor antagonist and IL-8 which was detectable by ELISA techniques 6 h after stimulation. This elevation returned to constitutive levels 24 or 48 h postinduction. TNFalpha secretion was detected in stimulated cells only after 48 h. These results suggest that SP can activate keratinocytes and support its role in the local inflammatory reaction.
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PMID:Substance P and keratinocyte activation markers: an in vitro approach. 893 86

The purpose of this study was to determine whether interleukin-1 beta (IL-1 beta) elicits macromolecular efflux from the in situ oral mucosa and whether it amplifies that evoked by bradykinin. Using intravital microscopy, we found that suffusion of recombinant human IL-1 beta (50 ng/ml) had no significant effects on leaky site formation and increase in clearance of fluorescein isothiocyanate-labeled dextran (mol mass 70 kDa) from the hamster cheek pouch. However, it significantly potentiated bradykinin-induced macromolecular efflux (P < 0.05). The potentiating effects of IL-1 beta on bradykinin-induced responses were abrogated by a bradykinin B2-receptor antagonist and by a recombinant human IL-1-receptor antagonist. They were not mediated by substance P, prostaglandins, or changes in vasomotor tone. IL-1 beta had no significant effects on adenosine-induced macromolecular efflux. Collectively, these data indicate that IL-1 beta potentiates bradykinin-induced macromolecular efflux from the in situ hamster oral mucosa in a specific fashion. We suggest that this interaction could play a role in the pathogenesis of oral mucosa inflammation.
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PMID:Interleukin-1 beta potentiates bradykinin-induced macromolecular efflux from hamster oral mucosa. 903 21

The neuropeptide substance P (SP) stimulates CFU in bone marrow (BM) cultures. Although the methylcellulose matrix used in these assays does not provide an appropriate substratum to support adherent-dependent cells, we have observed that cultures containing optimal SP (10(-8)-10(-10) M) develop confluent areas of reticular/fibroblastoid-like cells with CFUs predominantly localized within their vicinity. Characterization (cytochemical and immunofluorescence) of the reticular/fibroblastoid-like cells indicated that they were fibroblasts, the major constituent of the BM stroma. Hemopoietic effects by SP are mediated by the stroma that expresses SP receptors. We studied the effects of SP (10(-7)-10(-11) M) with suboptimal platelet-derived growth factor-BB (PDGF-BB; 5 ng/ml) and IL-1alpha (2 ng/ml), two fibrogenic cytokines, and also hemopoietic regulators. SP by itself and in synergy with either cytokine induced fibroblast proliferation. At optimum SP, IL-1alpha induced 1.6 times the proliferation of PDGF-BB (87 +/- 7 vs 55 +/- 5; n = 12; p < 0.05). The effects of SP were blunted by a specific neurokinin-1 antagonist. Scatchard analysis indicated that SP binds to BM fibroblasts with an approximate Kd of 5 nM. SP induced steady state mRNA for IL-1 receptor IL-1RI and PDGF-BB (PDGF-AR, PDGF-BR) receptors by 7.5-, 6.2-, and 10.5-fold, respectively. Their up-regulation may be partly responsible for the synergistic effects of SP and their ligands. Induction (3-fold) of neurokinin-1 mRNA by IL-1alpha compared with no induction by PDGF-BB may explain the preferred synergism between SP and IL-1alpha. This study indicates that induction of SP, IL-1alpha, and PDGF-BB receptors is important to their synergistic effects on BM fibroblast proliferation. These results bring new insights into stroma-mediated hemopoietic regulation.
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PMID:Receptor induction regulates the synergistic effects of substance P with IL-1 and platelet-derived growth factor on the proliferation of bone marrow fibroblasts. 912 Mar 2


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