Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stress is known to induce abortions, but underlying mechanisms are unknown. Both alloimmunization and injection of antibody to the asialoGM1 determinant of natural killer cells have been shown to prevent stress-triggered abortion in mice. DBA/2J-mated CBA/J female mice were used to investigate the influence of stress during early gestation on systemic hormone levels and on cytokines in the decidua that are thought to be relevant to abortion in nonstress-related murine abortion. Lowered levels of progesterone did not occur as a result of stress. In stressed mice, increased levels of the abortogenic cytokine tumor necrosis factor alpha (TNF alpha) were associated with decreased levels of pregnancy-protective transforming growth factor beta 2-related suppressive activity in uterine decidua. In the alloimmunized animals where stress failed to boost the abortion rate, these effects were abrogated. Production of TNF alpha may be stimulated by the neurotransmitter substance P (SP); after injection of an SP receptor antagonist or SP-antibody, stress failed to increase the abortion rate above the background level. The increased levels of TNF alpha we observed in the stressed animals were completely abrogated in the animals that had received the SP receptor antagonist; stress also failed to decrease the pregnancy-protective suppressive activity in the decidua of these animals. The data indicate that stress may inhibit protective suppressor mechanisms and promote secretion of abortogenic cytokines such as TNF alpha via neurotransmitter SP.
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PMID:Stress-induced murine abortion associated with substance P-dependent alteration in cytokines in maternal uterine decidua. 854 75

Previous studies from this laboratory had shown that exposure of mice to cold water stress leads to an increase in the secretion of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF alpha) from their peritoneal macrophages. We now report that the secretion of IL-6 from peritoneal macrophages is also increased after cold water stress and that the peptide substance P (SP) participates in this stress-induced response. The stress paradigm involved subjecting male C57BL/6J mice to 5 min swim tests in 10 +/- 2 degrees C water twice daily for 4 d. Cold water stress augments the lipopolysaccharide-induced IL-6 secretion from peritoneal macrophages, elevates immunoreactive SP (iSP) in the peritoneal wash fluid, and reduces iSP in certain peritoneum-containing tissues or organs (i.e., diaphragm, abdominal wall, ileum, and rectum). The 10 d stress time studies indicate that increased IL-6 secretion is positively related to elevated iSP in the peritoneal wash fluid and inversely related to reduced iSP in certain peritoneum-containing tissues. Pretreatment with capsaicin, which depletes SP in the sensory nerve endings, eliminates stress-control differences in the peritoneal wash fluid and in certain peritoneal tissues. Moreover, RP67,580, a specific SP antagonist, eliminates the cold water stress-induced augmentation of IL-6 secretion from peritoneal macrophages. These results suggest that cold water stress promotes the release of SP from peritoneal tissues into the peritoneal cavity, where it participates in the cold water stress-induced macrophage functional alterations.
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PMID:Endogenous substance P mediates cold water stress-induced increase in interleukin-6 secretion from peritoneal macrophages. 864 17

Substance P (SP), a member of the tachykinin family of neuropeptides, is an important immunomodulator of lymphocyte and monocyte/macrophage function. We have examined the effects of SP on human immunodeficiency virus type 1 (HIV-1) infection of peripheral blood monocyte-derived macrophages (MDMs) in vitro. Human monocytes isolated by Ficoll gradient followed by adherence were maintained in vitro for 10 days and infected with HIV-1. The addition of SP resulted in a 2- to 8-fold-enhanced HIV-1 expression in the MDMs isolated from 7 of 13 healthy donors as determined by reverse transcriptase (RT) activity and p24 protein expression assays, as compared to control cultures incubated with HIV-1 alone. There was no correlation observed, however, between SP-stimulated TNF production and HIV-1 expression in MDMs obtained from a subset of these donors. These effects of SP on HIV-1 expression in MDMs in vitro may have in vivo implications relevant to modulation of monocyte/macrophage functions, to HIV-1 infection of monocytes/macrophages, and to the immunopathogenesis of HIV-1 infection.
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PMID:Substance P modulates human immunodeficiency virus replication in human peripheral blood monocyte-derived macrophages. 883 96

The TNF receptor fusion protein, Ro 45-2081, inhibited allergic and non-allergic inflammatory responses in the airways. Treatment of sensitized guinea-pigs with Ro 45-2081 reduced allergen-induced influx of inflammatory cells into the lungs, abolished edema formation and inhibited hyperreactivity to substance P. Administration of Ro 45-2081 after allergen challenge reversed the influx of inflammatory cells into the lungs. Sephadex-induced neutrophil influx into the lungs of rats was also blocked by Ro 45-2081. The effects of Ro 45-2081 suggest that inhibitors of TNF may have potential as therapeutics for inflammatory diseases in the lung.
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PMID:Ro 45-2081, a TNF receptor fusion protein, prevents inflammatory responses in the airways. 942 30

There is increasing experimental evidence that the neurologic system can directly participate in cutaneous inflammation and wound healing. Recent studies indicate that neuropeptides released by cutaneous nerves such as c-fibers can activate a number of target cells including keratinocytes, Langerhans cells, mast cells, and endothelial cells. One such neuropeptide, substance P (SP), is able to specifically bind to murine and human keratinocytes and induce the release of cytokines such as interleukin 1 (IL-1). Other studies demonstrate that SP can also activate mast cells to produce the potent pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha). More recently, we examined the effect of cutaneous neuropeptides on human dermal microvascular endothelial cell (HDMEC) activities. Our studies indicate that the c-fiber-derived calcitonin gene-related peptide (CGRP) is capable of stimulating HDMEC to secrete the neutrophil chemotactic factor interleukin 8 (IL-8). In addition, SP is able to directly activate HDMEC to express high levels of the important cellular adhesion molecule vascular cellular adhesion molecule 1 (VCAM-1). Thus, these studies support the role that the neurologic system may play in mediating the biologic processes that occur during inflammation and wound healing in the skin.
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PMID:Interactions of the skin and nervous system. 948 11

Explants of tissue derived from the medial collateral ligament (MCL) of normal and pregnant NZW rabbits cultured in the presence of substance P (SP), calcitonin gene-related peptide (CGRP), or both neuropeptides were found to have altered mRNA levels for a number of relevant molecules. Using a very efficient RNA isolation method, semi-quantitative RT-PCR and rabbit-specific primers, mRNA for growth factors (TGFbeta, bFGF, IGF-2, ET-1), cytokines (IL-1, TNF), enzymes (COX-2, iNOS), metalloproteinases (collagenase, stromelysin) and metalloproteinase inhibitors (TIMP-1, TIMP-2) were assessed after culture with or without neuropeptide. The results indicate that SP was effective in lowering mRNA levels for all of the molecules assessed in RNA from normal ligaments except IL-1beta, IGF-2 and TIMP-1, for which there was no significant effect. Similarly, CGRP was effective in lowering mRNA levels for all molecules except TNF, ET-1 and the TIMPs. The extent of the lowering of mRNA levels was both molecule-specific and neuropeptide-specific. When the experiments were repeated with ligament tissue from pregnant animals, a very different pattern of responsiveness to the neuropeptides was observed. While mRNA levels for 9/12 genes assessed were significantly affected by SP when normal MCL tissue was investigated, pregnancy abolished all significant responsiveness to this neuropeptide except for iNOS mRNA levels. In the case of iNOS mRNA, SP induced an increase in the steady-state levels, the opposite to what was observed with tissue from non-pregnant animals. For CGRP and SP+CGRP, tissue from pregnant animals was still responsive, but the pattern of responsiveness was changed from strictly a lowering of steady-state mRNA levels to elevations in mRNA levels for a number of genes. These findings indicate that mRNA levels for a number of genes can be influenced by neuropeptides known to be in ligaments. Thus, neuropeptides likely are important regulators of ligament cell metabolism. As the responsiveness to SP was nearly completely abolished during pregnancy, neuroregulatory influences mediated by this peptide are altered in the pregnant female. This loss of responsiveness to SP may also be one aspect of the analgesia associated with pregnancy.
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PMID:Pregnancy alters the in vitro responsiveness of the rabbit medial collateral ligament to neuropeptides: effect on mRNA levels for growth factors, cytokines, iNOS, COX-2, metalloproteinases and TIMPs. 978 99

Tumour necrosis factor-alpha (TNF alpha) was studied in the carrageenin (CG) induced knee-joint incapacitation, and also in mediating recurrent incapacitation response in knee-joints previously exposed to an inflammatory attack. CG or TNF alpha intra-articular injection into CG-primed knee-joints induced an intense and long-lasting (>8 h) peaking incapacitation response. TNF alpha injected in naive joints did not elicit incapacitation. Anti-TNF alpha serum in situ treatment specifically inhibited CG-induced incapacitation in naive joints, and also TNF alpha-induced incapacitation in primed joints. Hoe-140 (D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin, a bradykinin B2 receptor antagonist, given before CG, abolished incapacitation, but was without effect when injected 3 h after. Hoe-140 given before or after the CG injection in primed joints was without effect, but it produced a partial inhibitory effect in the early phase (1 h) of TNF alpha-induced incapacitation. Des-Arg9[Leu3]-bradykinin, a bradykinin B1 receptor antagonist, given intra-articularly after CG or TNF alpha, reversed incapacitation either in naive or primed joints. Indomethacin abolished the incapacitation induced by CG in naive joints, but only the 5-lipoxygenase inhibitor MK-886 plus indomethacin blocked the response in primed joints. MK-886 did not modify CG-induced incapacitation in naive joints, but lately reversed CG-induced incapacitation in primed joints, and blocked TNF alpha-induced response. Substance P or prostaglandin E2 did not induce incapacitation in either naive or primed joints. Our results support the conclusion that TNF alpha is a mediator of CG-induced inflammatory incapacitation, and is able to induce the further release of kinins and leukotrienes, which is suggested to have an important role in the maintenance of long-lasting nociceptive response.
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PMID:Tumour necrosis factor-alpha mediates carrageenin-induced knee-joint incapacitation and also triggers overt nociception in previously inflamed rat knee-joints. 1042 63

Contact hypersensitivity (CH)-induction begins when cutaneous antigen-presenting cells (APC) capture hapten that has been applied epicutaneously, and the process prepares hapten for presentation to T-cells. APCs are functionally plastic, are influenced by the microenvironment in which they reside, and their functional properties have a profound effect on the phenotype of the hapten-specific T-cells that they activate. Ultraviolet B radiation (UVR) distorts the cutaneous microenvironment, thereby altering local APC function, and changing the immune outcome from sensitization to unresponsiveness. Although UVR induces keratinocytes to produce TNF alpha and IL-10 (cytokines that have been implicated in failed CH-induction and tolerance, respectively, after UVR), dermal mast cells turn out to be the source of these immunomodulatory cytokines. Mast cell degranulation is triggered by CGRP released from UVR-exposed cutaneous nerve termini. Even in normal skin, cutaneous nerves influence the immune response to haptens. Substance P released from cutaneous nerves acts as an adjuvant, raising the immunogenicity of epicutaneously applied haptens. Thus, the nerves and the neuropeptides that these processes release contribute to the cutaneous microenvironment. By altering APC function, cutaneous nerves can dictate the quality and the quantity of immune responses to antigens of the skin.
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PMID:Neural influences on induction of contact hypersensitivity. 1081 53

Neuropeptides and neurohormones have been shown to be able to regulate cutaneous immune reactions. Binding of beta-endorphin (beta-end) on epidermal Langerhans cells (LC) and effects of beta-end on cytokine expression were examined. Biotinylated beta-end bound to the mouse LC-like cell line, XS52, and the binding was replaced with intact beta-end but not with substance P. beta-End augmented secretion of IL-1 beta and IL-10 from XS52 cells were induced by a combination of LPS and GM-CSF. Induction of TNF alpha was suppressed by beta-end. The regulation of cytokine expression was confirmed in fresh LC by RT-PCR. These results suggest that beta-end is a regulator of skin immune function.
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PMID:beta-Endorphin binding and regulation of cytokine expression in Langerhans cells. 1081 76

Substance P plays an important role in neurogenic inflammation with granulocyte infiltration. To investigate cytokines involved in the substance P-induced inflammation and the mechanism of cell activation, we studied the release of TNF (tumor necrosis factor)-alpha and histamine from human skin slices in response to substance P and antigen. Substance P induced the release of histamine and TNF-alpha in a dose-dependent manner at concentrations from 0.8 to 100 microM. PD 098059 (2'-amino-3'-methoxyflavone) selectively inhibited the release of TNF-alpha, but not the release of histamine induced by either substance P or antigen. SB 203580 ([4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-++ +imida zole]) slightly inhibited TNF-alpha release induced by antigen, but not that induced by substance P, and slightly enhanced histamine release induced by either stimulation. The release of TNF-alpha in response to either stimulation was inhibited by 1 nM-1 microM dexamethasone, but histamine release was not affected. These results suggest that substance P, in addition to antigen, induced TNF-alpha release from human skin by a mitogen-activated protein (MAP) kinase, predominantly extracellular signaling-regulated protein kinase (ERK)-dependent, and dexamethasone-sensitive pathway, which is separate from that for histamine release from mast cells.
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PMID:Substance P induces tumor necrosis factor-alpha release from human skin via mitogen-activated protein kinase. 1085 44


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