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)

Previously, we have shown that primary afferent neurons are necessary for disease activity in immune-mediated liver injury in mice. These nerve fibers are detectable by substance P (SP) immunocytochemistry in the portal tract of rodent liver. Antagonists of the neurokinin-1 receptor (NK-1R), which is the prime receptor of SP, prevented liver damage by suppressing the synthesis of proinflammatory cytokines. Here, we investigated the influence of primary afferent nerve fibers, SP, and NK-1 receptor antagonists on hepatocyte apoptosis in vivo induced by administration of activating anti-CD95 monoclonal antibody (mAb) to mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment prevented CD95-mediated activation of caspase-3, measured as enzymatic activity in liver homogenates or by demonstration of hepatocellular immunoreactivity for active caspase-3 in liver slices, and liver damage. This effect was reversed by administration of SP to anti-CD95 mAb-treated mice depleted from primary afferent neurons. The presence of the NK-1R on mouse hepatocytes was demonstrated by immunocytochemistry and flow cytometry. Intraperitoneal pretreatment with the NK-1 receptor antagonists (2S,3S)-cis-2-(diphenylmethyl)-N-([2-methoxyphenyl]-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) or (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperadine (L-733,060) dose dependently protected mice from CD95-mediated liver injury. Similar results were obtained when apoptotic liver damage was induced by administration of tumor necrosis factor-alpha to d-galactosamine-sensitized mice. In conclusion, SP, probably by binding to its receptor on hepatocytes, might aggravate apoptotic signals in these cells. Because NK-1 receptor antagonists not only suppress the proinflammatory cytokine response in the liver but also prevent liver cell apoptosis in vivo, they might be suitable drugs for treatment of immune-mediated liver disease.
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PMID:Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-alpha-mediated apoptotic liver damage. 1461 92

We previously described a rat model where the injection of formalin in the tail induced a facilitation of the hindpaw withdrawal reflexes (hyperalgesia). In the present work, after injecting formalin in the tail, we measured the levels of pro-nociceptive mediators tumor necrosis factor-alpha (TNF) and substance P (SP) in the rat paws. A significant increase of SP levels was evident in the hindpaw, whereas no changes in SP were observed in the forepaw. Both in the hindpaw and in the forepaw the TNF levels were higher than normal at each stage of measurement. Our results indicate that a prolonged neuronal activation induced by formalin injection is associated with a change in nociceptive and inflammatory mediators in distal sites of the body. The fact that SP levels are changed in the hindpaw but not in the forepaw might point to the activation of a mechanism of retrograde signaling from central synapses to paw afferent nerves.
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PMID:Increased substance P and tumor necrosis factor-alpha level in the paws following formalin injection in rat tail. 1530 60

Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of proinflammatory cytokines from colonic epithelial cells. SP also stimulates cell proliferation, a critical event in tissue healing during chronic colitis, via transactivation of the epidermal growth factor (EGF) receptor (EGFR) and activation of mitogen-activated protein kinase (MAPK). Here we examined the mechanism by which SP induces EGFR and MAPK activation. We used non-transformed human NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) as well as untransfected U373 MG cells expressing high levels of endogenous NK-1R. Exposure of both cell lines to SP (10(-7) m) stimulated EGFR activation (1 min) followed by extracellular signal-regulated protein kinase (ERK1/2) activation (2-5 min). SP-induced ERK1/2 activation was blocked by pretreatment with the metalloproteinase inhibitor Batimastat/GM6001, the EGFR phosphorylation inhibitor AG1478, and the tumor necrosis factor-alpha-converting enzyme (TACE) inhibitor TAPI-1. Pretreatment with antibodies against potential EGFR ligands suggested that transforming growth factor-alpha (TGFalpha), but not the other EGFR ligands EGF, heparin-binding EGF, or amphiregulin, mediates SP-induced EGFR transactivation. SP stimulated TGFalpha release into the extracellular space that was measurable within 2 min, and this release was inhibited by metalloproteinase inhibitors and the TACE inhibitor TAPI-1. SP also induced MAPK-mediated cell proliferation that was inhibited by TACE, matrix metalloproteinase (MMP), EGFR, and MEK1 inhibitors. Thus, in human colonocytes, NK-1R-induced EGFR and MAPK activation and cell proliferation involve matrix metalloproteinases (most likely TACE) and the release of TGFalpha. These signaling mechanisms may be involved in the protective effects of NK-1R in chronic colitis.
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PMID:Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes. 1531 41

This study was undertaken to clarify the mechanisms by which C-fiber degeneration at neonatal stages exacerbates the inflammatory responses of rat airways. Rats were treated with capsaicin at neonatal stages and immunized with ovalbumin (OVA) at adult ages. Challenge of capsaicin-pretreated rats with OVA promoted a higher influx of neutrophils in bronchoalveolar lavage (BAL) fluid compared with the vehicle group. No significant differences were found for the other cell types. The increased adhesion of N-formyl-methionyl-leucyl-phenylalanine (fMLP; 0.1 microM)- and phorbol myristate acetate (PMA; 1 microM)-treated neutrophils to fibronectin-coated wells did not differ among vehicle- and capsaicin-pretreated rats. Additionally, fMLP (10 microM), platelet-activating factor (0.1 microM), and substance P (50 microM) induced a significant neutrophil chemotaxis, but no differences were found among vehicle and capsaicin groups. Increased levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, and leukotriene B4 in BAL fluid as well as higher expression of cytokine-induced neutrophil chemoattractant (CINC)-3 in lung homogenates were detected in the capsaicin group compared with vehicle group. In the capsaicin group, chronic treatment with compound 48/80 restored the TNF-alpha levels to control values and prevented the neutrophil influx in BAL fluid. The enhanced production of TNF-alpha, superoxide anion, and nitrite by isolated alveolar macrophages in response to lipopolysaccharide (3 microg/ml), PMA (10 nM), and/or zymosan (100 particles/cell) did not differ between vehicle- and capsaicin-pretreated rats. In conclusion, chronic neuropeptide depletion promoted by neonatal capsaicin treatment up-regulates airways mast cells, which upon activation by antigen at adult ages, release large amounts of cytokines such as TNF-alpha and CINC-3 that accounts for the massive airways neutrophil infiltration.
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PMID:Mechanisms involved in the enhancement of allergic airways neutrophil influx by permanent C-fiber degeneration in rats. 1557 95

1 Substance P (SP) is deeply involved in lung pathophysiology and plays a key role in the modulation of inflammatory-immune processes. We previously demonstrated that SP activates guinea-pig alveolar macrophages (AMs) and human monocytes, but a careful examination of its effects on human AMs is still scarce. 2 This study was undertaken to establish the role of SP in human AM isolated from healthy smokers and non-smokers, by evaluating the presence of tachykinin NK(1) receptors (NK-1R) and SP's ability to induce superoxide anion (O(2)(-)) production and cytokine release, as well as activation of the nuclear factor-kappaB (NF-kappaB) pathway. 3 By Western blot analysis and immunofluorescence, we demonstrate that authentic NK-1R are present on human AMs, a three-fold enhanced expression being observed in healthy smokers. These NK-1R are functional, as SP and NK(1) agonists dose-dependently induce O(2)(-) production and cytokine release. In AMs from healthy smokers, SP evokes an enhanced respiratory burst and a significantly increased release of tumor necrosis factor-alpha as compared to healthy non-smokers, but has inconsistent effects on IL-10 release. The NK(1) selective antagonist CP 96,345 ((2S,3S)-cis-2-diphenylmethyl-N[(2-methoxyphenyl)-methyl]-1-azabicyclo-octan-3-amine)) competitively antagonized SP-induced effects. 4 SP activates the transcription factor NF-kappaB, a three-fold increased nuclear translocation being observed in AMs from healthy smokers. This effect is receptor-mediated, as it is reproduced by the NK(1) selective agonist [Sar(9)Met(O(2))(11)]SP and reverted by CP 96,345. 5 These results clearly indicate that human AMs possess functional NK-1R on their surface, which are upregulated in healthy smokers, providing new insights on the mechanisms involved in tobacco smoke toxicity.
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PMID:Expression of functional NK1 receptors in human alveolar macrophages: superoxide anion production, cytokine release and involvement of NF-kappaB pathway. 1577 38

Myofascial pain associated with myofascial trigger points (MTrPs) is a common cause of nonarticular musculoskeletal pain. Although the presence of MTrPs can be determined by soft tissue palpation, little is known about the mechanisms and biochemical milieu associated with persistent muscle pain. A microanalytical system was developed to measure the in vivo biochemical milieu of muscle in near real time at the subnanogram level of concentration. The system includes a microdialysis needle capable of continuously collecting extremely small samples (approximately 0.5 microl) of physiological saline after exposure to the internal tissue milieu across a 105-microm-thick semi-permeable membrane. This membrane is positioned 200 microm from the tip of the needle and permits solutes of <75 kDa to diffuse across it. Three subjects were selected from each of three groups (total 9 subjects): normal (no neck pain, no MTrP); latent (no neck pain, MTrP present); active (neck pain, MTrP present). The microdialysis needle was inserted in a standardized location in the upper trapezius muscle. Due to the extremely small sample size collected by the microdialysis system, an established microanalytical laboratory, employing immunoaffinity capillary electrophoresis and capillary electrochromatography, performed analysis of selected analytes. Concentrations of protons, bradykinin, calcitonin gene-related peptide, substance P, tumor necrosis factor-alpha, interleukin-1beta, serotonin, and norepinephrine were found to be significantly higher in the active group than either of the other two groups (P < 0.01). pH was significantly lower in the active group than the other two groups (P < 0.03). In conclusion, the described microanalytical technique enables continuous sampling of extremely small quantities of substances directly from soft tissue, with minimal system perturbation and without harmful effects on subjects. The measured levels of analytes can be used to distinguish clinically distinct groups.
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PMID:An in vivo microanalytical technique for measuring the local biochemical milieu of human skeletal muscle. 1603 3

We examined whether soluble mediators regulate the expression of tachykinin receptor mRNAs in synovial fibroblasts of patients with rheumatoid arthritis (RA). mRNAs encoding long and short isomers of neurokinin 1 receptor (NK1R), and neurokinin 2 receptor (NK2R) were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Level of long, but not the short, of NK1R mRNA was increased by treatment with 10-100 ng/ml basic fibroblast growth factor (bFGF) or 20 ng/ml tumor necrosis factor-alpha (TNF-alpha), but not with 1ng/ml interleukin 1beta (IL-1beta). TNF-alpha upregulated NK2R mRNA as well as long NK1R mRNA whereas bFGF had no effect on NK2R mRNA. Expression of neurokinin 3 receptor (NK3R) mRNA was not observed in RA fibroblasts, and its expression was not induced by bFGF and TNF-alpha. The basal and increased levels of long NK1R mRNA were inhibited by treatment with 20 microM SU5402, an inhibitor of the tyrosine kinase activity of FGF receptor 1 (FGFR1), or 10 ng/ml transforming growth factor-beta1 (TGF-beta1). SU5402 and TGF-beta1 had no effect on the basal level of short NK1R mRNA. Immunocytochemistry revealed the enhancement by bFGF of immunoreactive NK1Rs in the cells at 24 h after treatment. These results suggest that bFGF, TGF-beta1, and TNF-alpha in synovial tissue and fluid play a role in the regulation of long NK1R expression in synovial fibroblasts of RA patients. It appears that the pathway of downregulation by TGF-beta1 is more dominant in the long NK1R mRNA expression than that of upregulation by bFGF or TNF-alpha. Furthermore, the regulation of short NK1R mRNA expression seems to be performed via a different pathway from that of long isomer mRNA.
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PMID:Regulation of neurokinin-1 receptor messenger RNA expression in synovial fibroblasts of patients with rheumatoid arthritis. 1615 93

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.
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PMID:Cytokine dysregulation, inflammation and well-being. 1616 5

Several of the proinflammatory peptides involved in rheumatoid arthritis pathogenesis, including peptides induced downstream of tumor necrosis factor-alpha as well as the monocyte/T cell-attracting chemokines RANTES and stromal cell-derived factor (SDF)-1alpha and the neuropeptides vasoactive intestinal peptide (VIP) and substance P, have their biological half-lives controlled by dipeptidyl peptidase IV (DPPIV). Proteolysis by DPPIV regulates not only the half-life but also receptor preference and downstream signaling. In this article, we examine the role of DPPIV homologs, including CD26, the canonical DPPIV, and their substrates in the pathogenesis of rheumatoid arthritis. The differing specific activities of the DPPIV family members and their differential inhibitor response provide new insights into therapeutic design.
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PMID:Dipeptidyl peptidase IV activity and/or structure homologs: contributing factors in the pathogenesis of rheumatoid arthritis? 1627 1

Lipopolysaccharide (LPS), a bacterial membrane endotoxin, induces a systemic inflammatory response (IFR) through the activation of blood monocytes and hepatic kupffer cells. These cells secrete pro-inflammatory cytokines, which subsequently activate the hypothalamic-pituitary-adrenal axis (HPAA) to release cortisol, an anti-inflammatory hormone that regulates the IFR and subsequent immune response (IR). The intent of this study was to characterize the acute phase response in female sheep challenged systemically with a range of doses of Escherichia coli endotoxin. Yearling ewes were challenged with an i.v. bolus dose of LPS (0, 200, 400, 600 ng/kg BW) and the acute phase response assessed by measuring serum interleukin (IL)-6 and cortisol concentrations, and the febrile response over time. A follow-up liver biopsy study was performed to determine kinetic differences in the expression of eight candidate hepatic genes between LPS dose groups using real-time RT-PCR. The initial time trail did not follow a linear dose response relationship with respect to the febrile and HPAA response to LPS challenge. Serum IL-6 concentrations increased in the two highest treatment groups but did not correlate with the observed febrile and HPAA response. The expression of Toll-like receptor 4, CD14, IL-6, tumor necrosis factor-alpha, IL-1beta, macrophage migration inhibitory factor, 11-beta-hydroxysteroid dehydrogenase (HSD), and tachykinin precursor 1 hepatic genes was dependent on both the dose and the kinetics of the response to LPS.
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PMID:Assessment of the ovine acute phase response and hepatic gene expression in response to Escherichia coli endotoxin. 1680 92


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