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)

Stimulation of sensory nerves can lead to release of peptides such as substance P (SP) and consequently to neurogenic inflammation. We studied the role of bacterial lipopolysaccharide (LPS) in regulating SP-induced inflammation. Experimental cystitis was induced in female mice by intravesical instillation of SP, LPS, or fluorescein-labeled LPS. Uptake of fluorescein-labeled LPS was determined by confocal analysis, and bladder inflammation was determined by morphological analysis. SP was infused into the bladders of some mice 24 h after exposure to LPS. In vitro studies determined the capacity of LPS and SP to induce histamine and cytokine release by the bladder. LPS was taken up by urothelial cells and distributed systemically. Twenty-four hours after instillation of LPS or SP, bladder inflammation was characterized by edema and leukocytic infiltration of the bladder wall. LPS pretreatment enhanced neutrophil infiltration induced by SP, increased in vitro release of histamine, tumor necrosis factor-alpha, and interferon-gamma, and significantly reduced transforming growth factor-beta1 release. These findings suggest that LPS amplifies neurogenic inflammation, thereby playing a role in the pathogenesis of neurogenic cystitis.
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PMID:LPS-sensory peptide communication in experimental cystitis. 1178 33

1 To evaluate the role of prostaglandin I(2) (PGI(2)) in allergic inflammation, allergic responses in the airway, skin and T cells were studied in mice lacking the receptor for PGI(2) (the prostanoid IP receptor) through gene disruption. 2 Three inhalations of antigen caused an increase in plasma extravasation, leukocyte accumulation and cytokine (interleukin (IL)-4 and IL-5) production in the airway of sensitized mice. These airway inflammatory responses were significantly greater in IP receptor deficient mice than in wild-type mice. 3 The vascular leakage caused by passive cutaneous anaphylaxis, substance P and 5-hydroxytryptamine was markedly increased in the skin of IP receptor deficient mice, compared with comparably treated wild-type mice. 4 The inhalation of antigen in sensitized mice resulted in increased serum antigen specific IgE, total IgE and IgG levels. The magnitude of the elevations of each immunoglobulin level in IP receptor deficient mice is notably higher than that in wild-type mice. To elucidate the mechanism of an enhancement of immunoglobulin production, the activity of T cells in sensitized and non-sensitized mice was studied by means of the production of cytokines. The antigen-induced IL-4 production by spleen cells from sensitized IP receptor deficient mice was almost three times greater than that in wild-type mice. On the contrary, the anti-CD3 antibody-induced interferon-gamma production by CD4(+) T cells from non-sensitized IP receptor deficient mice was significantly lower than that in wild-type mice. 5 The present data indicate that IP receptor deficiency reinforced an allergic airway and skin inflammation by augmentation of vascular permeability increase and the T helper 2 cell function. These findings suggest a regulatory role of PGI(2) in allergic inflammation.
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PMID:Augmentation of allergic inflammation in prostanoid IP receptor deficient mice. 1223 50

A neuropeptide substance P is related to skin inflammation. Interferon-induced protein of 10 kDa (IP-10) chemoattracts T helper 1 cells, and interferon-induced protein of 10 kDa production by keratinocytes is enhanced in inflammatory skin diseases such as psoriasis. We examined the in vitro effects of substance P on interferon-induced protein of 10 kDa production by human keratinocytes. Though substance P alone did not induce interferon-induced protein of 10 kDa production, it enhanced interferon-induced protein of 10 kDa secretion, mRNA expression, and promoter activity induced by suboptimal concentrations of interferon-gamma. Interferon-stimulated response element and two nuclear factor-kappaB sites on interferon-induced protein of 10 kDa promoter were responsible for the enhancement by substance P. Substance P alone enhanced transcriptional activity and transcription factor binding through the two nuclear factor-kappaB sites, whereas it did not alter interferon-gamma-induced transcriptional activity and transcription factor binding through interferon-stimulated response element. The effects of substance P on interferon-induced protein of 10 kDa production and nuclear factor-kappaB activation were inhibited by neurokinin-1 receptor antagonist, phospholipase C inhibitor, intracellular Ca2+ chelator, and anti-oxidant. These results suggest that substance P may induce nuclear factor-kappaB activation and interferon-induced protein of 10 kDa production in synergy with interferon-gamma via neurokinin-1 receptor on keratinocytes. These effects of substance P may be mediated via phospholipase C activation, intra-cellular Ca2+ signal, and reactive oxygen intermediates.
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PMID:Substance P enhances the production of interferon-induced protein of 10 kDa by human keratinocytes in synergy with interferon-gamma. 1248 30

Previously, we have shown that primary afferent sensory neurons are necessary for disease activity in T cell-mediated immune hepatitis in mice. In the present study, we analyzed the possible role of substance P (SP), an important proinflammatory neuropeptide of these nerve fibers, in an in vivo mouse model of liver inflammation. Liver injury was induced by bacterial lipopolysaccharide (LPS) in D-galactosamine (GalN)-sensitized mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment down-regulated circulating levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) and protected mice from GalN/LPS-induced liver injury. Likewise, pretreatment of mice with antagonists of the SP-specific neurokinin-1 receptor (NK-1R), i.e., (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) and (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine (L-733,060), dose dependently protected mice from GalN/LPS-induced liver injury. The presence of the NK-1R in the murine liver was demonstrated by reverse transcription-polymerase chain reaction, sequence analysis, and immunocytochemistry. NK-1R blockade reduced inflammatory liver damage, i.e., edema formation, neutrophil infiltration, hepatocyte apoptosis, and necrosis. To get further insight into the mechanism by which receptor blockade attenuated GalN/LPS-induced liver damage, we analyzed plasma levels and intrahepatic expression of TNFalpha, IFNgamma, interleukin (IL)-6, and IL-10. NK-1R blockade clearly inhibited GalN/LPS-induced production of TNFalpha and IFNgamma, whereas synthesis of the hepatoprotective cytokines IL-6 and IL-10 was increased. NK-1 receptor antagonists might be potent drugs for treatment of inflammatory liver disease, most likely by inhibiting SP effects.
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PMID:Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury. 1264 50

In a well-established murine abortion model, stress is thought to trigger fetal rejection by inducing a proinflammatory immune response via substance P (SP), being tumour necrosis factor (TNF)-alpha-producing CD8+ T cells involved. Interestingly, the SP metabolite SP5-11 also binds to SP receptors and mediates SP-like effects on immune cells at sites of inflammation. No data were available regarding the effects of SP5-11 on pregnancy outcome in the CBA/J x DBA/2J abortion-prone combination. We investigated the influence of SP5-11 in contrast to stress or SP on the abortion rate and the cytokine production by lymphocytes as well as on the levels of CD8+ T cells. Stress and SP boosted the abortion rate and increased the percentage of type 1 [TNF-alpha, interferon-gamma, interleukin (IL)-12] and type 2 (IL-4 and IL-10) cytokine-producing lymphocytes in blood and decidua, predominantly CD8+ T cells. Interestingly, SP5-11 did not significantly affect the abortion rate or cytokine production in the decidua, while increasing the Th1 and Th2 cytokine production systemically. Our data suggest that stress and SP induce abortion by augmenting the local levels of TNF-alpha, which seems therefore to be a potent trigger of miscarriage. On the contrary, the SP metabolite SP5-11 only affects the systemic cytokine production without boosting the abortion rate in this experimental model.
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PMID:Stress and substance P but not the substance P-metabolite SP5-11 trigger murine abortion by augmenting TNF-alpha levels at the feto-maternal interface. 1639

Volatile organic compounds are the main substances causing multiple chemical sensitivity reactions in human. Our laboratory has previously showed that the exposure of low-level formaldehyde causes immunogenic and neurogenic inflammatory responses in mice. The aim of the present study was to investigate the effect of long-term, low-level toluene exposure on airway inflammatory responses in mice lung. We exposed female C3H mice to filtered air (0ppm) or 50ppm of toluene for 6h/day on 5days/week for 6 or 12 weeks in the whole body exposure chamber. One day following the last toluene exposure, we collected bronchoalveolar lavage fluid from each mouse and examined cellular infiltration and production of cytokines, chemokines, neurotrophins and substance P by using ELISA method. We found that the number of total cells and macrophages increased significantly in both 6 and 12-week-exposed mice. In addition, the production of interferon-gamma and substance P were decreased significantly and nerve growth factor was not affected in both 6 and 12-week-exposed mice. In contrast, neurotrophin-3 production in bronchoalveolar lavage fluid was significantly increased only in 12-week-exposed mice. Our findings suggest that long-term (12-week) exposure of mice to low-level toluene modulates airway inflammatory response via neurological signaling.
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PMID:Effect of long-term exposure to low-level toluene on airway inflammatory response in mice. 1717 43

During neuronal-induced inflammation, mast cells may respond to stimuli such as neuropeptides in an FcepsilonRI-independent manner. In this study, we characterized human mast cell responses to substance P (SP), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and compared these responses to human mast cell responses to immunoglobulin E (IgE)/anti-IgE and compound 48/80. Primary cultured mast cells, generated from CD34(+) progenitors in the presence of stem cell factor and interleukin-6 (IL-6), and human cultured mast cells (LAD2) were stimulated with these and other stimuli (gastrin, concanavalin A, radiocontrast media, and mannitol) and their degranulation and chemokine production was assessed. VIP and SP stimulated primary human mast cells and LAD cells to degranulate; gastrin, concanavalin A, radiocontrast media, mannitol, CGRP and NGF did not activate degranulation. While anti-IgE stimulation did not induce significant production of chemokines, stimulation with VIP, SP or compound 48/80 potently induced production of monocyte chemoattractant protein-1, inducible protein-10, monokine induced by interferon-gamma (MIG), RANTES (regulated on activation, normal, T-cell expressed, and secreted) and IL-8. VIP, SP and compound 48/80 also activated release of tumour necrosis factor, IL-3 and granulocyte-macrophage colony-stimulating factor, but not IL-4, interferon-gamma or eotaxin. Human mast cells expressed surface neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2 (VPAC2) but not VPAC1 and activation of human mast cells by IgE/anti-IgE up-regulated expression of VPAC2, NK2R, and NK3R. These studies demonstrate the pattern of receptor expression and activation of mast cell by a host of G-protein coupled receptor ligands and suggest that SP and VIP activate a unique signalling pathway in human mast cells. These results are likely to have direct relevance to neuronally induced inflammatory diseases.
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PMID:Neuropeptides activate human mast cell degranulation and chemokine production. 1792 33

Stressful life events evidently have an impact on development of allergic diseases, but the mechanism linking stress to pathological changes of immune system function is still not fully understood. The aim of our study was to investigate the relationship between stressful life events, neuropeptide and cytokine concentrations in children. Within the LISAplus (Life style-Immune system-Allergy) study, blood samples from children of 6 yr of age were analysed for concentration of the neuropeptides vasoactive intestinal peptide (VIP), somatostatin (SOM), substance P (SP) and the Th1/Th2 cytokines interferon-gamma (IFN-gamma) and interleukin (IL)-4. Life events such as severe disease or death of a family member, unemployment or divorce of the parents were assessed with a questionnaire filled in by the parents. For 234 children, blood analysis and questionnaire data regarding life events were available. Children with separated/divorced parents showed high VIP levels and high concentrations of the Th2 cytokine IL-4 in their blood. Severe diseases and death of a family member were neither associated with neuropeptide levels nor with cytokine concentrations. Unemployment of the parents was associated with decreased IFN-gamma concentrations in children's blood but not with neuropeptide levels, whereas children experiencing concomitant severe disease and death of a family member had reduced SP blood levels. The neuropeptide VIP might be a mediator between stressful life events and immune regulation contributing to the Th2 shifted immune response in children with separated/divorced parents. Unemployment of the parents was associated with immune regulation in children on the basis of a still unknown mechanism whereas reduced SP levels seem to have no effect on immune regulation.
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PMID:Relation between stressful life events, neuropeptides and cytokines: results from the LISA birth cohort study. 1831 35

Intestinal adhesions are bands of fibrous tissue that connect the loops of the intestine to each other, to other abdominal organs or to the abdominal wall. Fibrous tissue formation is regulated by the balance between plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (tPA), which reciprocally regulate fibrin deposition. Several components of the inflammatory system, including cytokines, chemokines, cell adhesion molecules and neuropeptide substance P, have been reported to participate in adhesion formation. We have used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the interferon-gamma (IFN-gamma) and signal transducer and activator of transcription-1 (STAT1) system. Natural killer T (NKT) cell-deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wild-type mice, suggesting that NKT cell IFN-gamma production is indispensable for adhesion formation. This response does not depend on STAT4, STAT6, interleukin-12 (IL-12), IL-18, tumor necrosis factor-alpha, Toll-like receptor 4 or myeloid differentiation factor-88-mediated signals. Wild-type mice increased the ratio of PAI-1 to tPA after cecal cauterization, whereas Ifng(-/-) or Stat1(-/-) mice did not, suggesting that IFN-gamma has a crucial role in the differential regulation of PAI-1 and tPA. Additionally, hepatocyte growth factor, a potent mitogenic factor for hepatocytes, strongly inhibited intestinal adhesion by diminishing IFN-gamma production, providing a potential new way to prevent postoperative adhesions.
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PMID:Interferon-gamma is a therapeutic target molecule for prevention of postoperative adhesion formation. 1834 12

Itching is the most important problem in atopic dermatitis and tacrolimus has been suggested to attenuate the itching by topical application. However, the anti-itch mechanism of tacrolimus has not been well elucidated. In the present study, an allergic dermatitis accompanied by frequent scratching behaviors was induced by repeated paintings with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse ear and the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior were comparatively examined. Repeated DNFB paintings caused a typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behaviors. Both tacrolimus and dexamethasone given topically for 10 days before the final challenge significantly inhibited the ear swelling and reduced the expression of interferon-gamma mRNA. Dexamethasone inhibited the accumulation of eosinophils completely, although tacrolimus did not. Both drugs did not affect the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior, whereas dexamethasone failed to affect it. Repeated DNFB challenge depleted substance P in the dermis. Treatment with tacrolimus before the final challenge completely inhibited the recovery of substance P content, whereas dexamethasone facilitated the recovery. DNFB-induced ear swelling and scratching behavior were significantly inhibited by FK888, a tachykinin NK(1) receptor antagonist. Therefore, substance P seems to participate in the induction of ear swelling and scratching behavior upon final challenge with DNFB, and depletion of substance P by tacrolimus in the dermis contributes to its inhibition of ear swelling and scratching behavior at least in part.
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PMID:Depletion of substance P, a mechanism for inhibition of mouse scratching behavior by tacrolimus. 1981 45


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