Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Substance P and other polycationic peptides are thought to stimulate mast cell degranulation via direct activation of G proteins. We investigated the ability of extracellularly applied substance P to translocate into mast cells and the ability of intracellularly applied substance P to stimulate degranulation. In addition, we studied by reverse transcription--PCR whether substance P-specific receptors are present in the mast cell membrane. To study translocation, a biologically active and enzymatically stable fluorescent analogue of substance P was synthesized. A rapid, substance P receptor- and energy-independent uptake of this peptide into pertussis toxin-treated and -untreated mast cells was demonstrated using confocal laser scanning microscopy. The peptide was shown to localize preferentially on or inside the mast cell granules using electron microscopic autoradiography with 125I-labeled all-D substance P and 3H-labeled substance P. Cell membrane capacitance measurements using the patch-clamp technique demonstrated that intracellularly applied substance P induced calcium transients and activated mast cell exocytosis with a time delay that depended on peptide concentration (delay of 100-500 s at concentrations of substance P from 50 to 5 microM). Degranulation in response to intracellularly applied substance P was inhibited by GDPbetaS and pertussis toxin, suggesting that substance P acts via G protein activation. These results support the recently proposed model of a receptor-independent mechanism of peptide-induced mast cell degranulation, which assumes a direct interaction of peptides with G protein alpha subunits subsequent to their translocation across the plasma membrane.
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PMID:Mechanism of peptide-induced mast cell degranulation. Translocation and patch-clamp studies. 980 67

Urocortin (Ucn) is related to corticotropin-releasing hormone (CRH), and both are released in the brain under stress where they stimulate CRH 1 and 2 receptors (CRHR). Outside the brain, they may have proinflammatory actions through activation of mast cells, which are located perivascularly close to nerve endings and degranulate in response to acute psychological stress. Here, we report that a concentration of intradermal Ucn as low as 10 nM induced dose-dependent rat skin mast cell degranulation and increased vascular permeability. This effect appeared to be equipotent to that of calcitonin gene-related peptide and neurotensin. Ucn-induced skin vasodilation was inhibited by pretreatment with the mast cell stabilizer disodium cromoglycate (cromolyn) and was absent in the mast cell-deficient W/Wv mice. The selective nonpeptide CRH receptor 1 antagonist, antalarmin and the nonselective peptide antagonist astressin both reduced vascular permeability triggered by Ucn but not that by Substance P or histamine. In contrast, the peptide antagonist alpha-helical CRH-(9-41) reduced the effect of all three. The vasodilatory effect of Ucn was largely inhibited by pretreatment with H1 receptor antagonists, suggesting that histamine is the major mediator involved in vitro. Neuropeptide depletion of sensory neurons, treatment with the ganglionic blocker hexamethonium, or in situ skin infiltration with the local anesthetic lidocaine did not affect Ucn-induced vascular permeability, indicating that its in situ effect was not mediated through the peripheral nervous system. These results indicate that Ucn is one of the most potent triggers of rat mast cell degranulation and skin vascular permeability. This effect of Ucn may explain stress-induced disorders, such as atopic dermatitis or psoriasis, and may lead to new forms of treatment.
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PMID:Potent mast cell degranulation and vascular permeability triggered by urocortin through activation of corticotropin-releasing hormone receptors. 1002 77

Substance P (SP) induces increased vascular permeability, vasodilatation and granulocyte infiltration upon intradermal injection. Studies with antagonists and mast cell-deficient mice have suggested that granulocyte infiltration in response SP is mediated by leukotriene (LT) B4 derived from mast cells. However, the release of LTB4 has not been detected using mast cells isolated from human skin. Here we report the release of LTB4, prostaglandin (PG) D2 and histamine from guinea pig skin tissue in response to SP. The release of these agents occurred in a dose-dependent manner over a concentration range of SP from 1 x 10(-6) to 3 x 10(-4) M. No detectable PGE2 was released at any concentration up to 3 x 10(-4) M SP. The kinetics of histamine release induced in response to SP was more rapid than that induced by antigen. By comparison, SP-induced and antigen-induced release of LTB4 and PGD2 were similar, but slower than the histamine release. In the absence of extracellular Ca2+, release of histamine and PGD2 in response to SP was partially impaired, but to a lesser extent than that induced by antigen. On the other hand, LTB4 release in response to both SP and antigen was abolished under the same conditions. These results indicate that SP induces the release of LTB4, as well as histamine and PGD2, in the skin most likely from mast cells by a mechanism which may be different from that of mediator release in response to antigen.
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PMID:Substance P- and antigen-induced release of leukotriene B4, prostaglandin D2 and histamine from guinea pig skin by different mechanisms in vitro. 1048 19

Calcitonin gene-related peptide (CGRP) released from sensory neurons, which are closely apposed to mast cells and blood vessels, mediates gastric hyperemia in response to acid challenge of the damaged mucosa. Substance P (SP) is coreleased with CGRP from sensory neurons, but the role of this peptide in gastric blood flow regulation is largely unknown. Chambered rat stomachs were exposed to 1.5 M NaCl and acidic saline after treatment with SP, aprotinin (serine protease inhibitor), and the mast cell stabilizers ketotifen and sodium cromoglycate (SCG). Gastric hyperemia (measured with a laser Doppler flow velocimeter) after hypertonic injury and acid challenge was nearly abolished by SP. Aprotinin infused together with SP and pretreatment with ketotifen and SCG before SP restored the gastric hyperemia. Ketotifen and SCG inhibited mast cell degranulation in SP-treated rats. Preservation of gastric hyperemia was correlated with improved mucosal repair. These data suggest that impaired hyperemia by SP during acid challenge of the gastric mucosa may be mediated by a mast cell-dependent mechanism involving the release of proteases from mast cells.
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PMID:Substance P may attenuate gastric hyperemia by a mast cell-dependent mechanism in the damaged gastric mucosa. 1056 13

Unregulated increasing of Tumor necrosis factor-alpha (TNF-alpha) could be pathogenic in inflammatory diseases. The aim of this study was to investigate the anti-inflammatory role of the Substance P-antagonists (SPAs) through the inhibition of histamine release (HR) and TNF-alpha production from mast cell. Rat peritoneal mast cells (PMC) stimulated with Substance P (SP), in the presence of SPAs or not, were analyzed for HR and TNF-alpha protein production. Competitive Polymerase Chain Reaction, with an internal standard competing with target cDNA for the same primers, was used to determine the TNF-alpha mRNA expression. We show that the increase of either HR and TNF-alpha levels in peritoneal (PMC) after induction with SP was inhibited by pre-incubation with SPA or with the Peptide 101 (P101), while the [D-Pro2, D-Phe7, D-Trp9]-SP (dSP) had no effect. Neuraminidase treatment suggests that dSP, as well as SP, interacts with sialic acid residues on the cell surface. Moreover, SPA and P101 also inhibit the release of histamine and TNF-alpha induced by dSP suggesting that a receptor-independent mechanism is involved. These data could be useful to better understand the mechanisms involved in the mast cell activation and TNF-alpha production in the inflammatory diseases where SP is involved.
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PMID:Mast cell production of TNF-alpha induced by substance P evidence for a modulatory role of substance P-antagonists. 1058 Jul 96

Mast cells derive from a distinct bone marrow precursor and mature in tissues under the influence of stem cell factor, nerve growth factor (NGF) and certain interleukins. Intracranial mast cells first appear in the meninges and are located perivascularly close to neurons. They can be activated by antidromic stimulation of the trigeminal nerve, as well as by acute immobilization stress. Substance P (SP) and corticotropin-releasing hormone (CRH) are particularly potent in stimulating mast cell release of vasoactive, inflammatory and nociceptive molecules. These findings have suggested that mast cells may be involved in neuroinflammatory conditions, such as migraines. In this study, dura mast cells were shown to have characteristics of connective tissue mast cells (CTMC) as they contained histamine, heparin and rat mast cell protease I (RMCP-I). Mast cells were localized close to SP-positive neurons immunocytochemically and mast cell-neuron contacts were also documented using scanning electron microscopy. Dura stimulated by SP and carbachol in situ released histamine. Preincubation of dura with estradiol slightly augmented histamine release by SP, an effect possibly mediated through estrogen receptors identified on dura mast cells. Acute stress by immobilization led to dura mast cell degranulation which was prevented by pretreatment with a neutralizing antibody to CRH or a CRH receptor antagonist. The present results further clarify the biology of intracranial mast cells and support their involvement in the pathophysiology of migraines which are precipitated or worsened by stress.
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PMID:Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo. 1059 82

Using intravital microscopy, we examined the role played by B(1) receptors in leukocyte trafficking across mouse mesenteric postcapillary venules in vivo. B(1) receptor blockade attenuated interleukin (IL)-1beta-induced (5 ng intraperitoneally, 2 h) leukocyte-endothelial cell interactions and leukocyte emigration ( approximately 50% reduction). The B(1) receptor agonist des-Arg(9)bradykinin (DABK), although inactive in saline- or IL-8-treated mice, caused marked neutrophil rolling, adhesion, and emigration 24 h after challenge with IL-1beta (when the cellular response to IL-1beta had subsided). Reverse transcriptase polymerase chain reaction and Western blot revealed a temporal association between the DABK-induced response and upregulation of mesenteric B(1) receptor mRNA and de novo protein expression after IL-1beta treatment. DABK-induced leukocyte trafficking was antagonized by the B(1) receptor antagonist des-arg(10)HOE 140 but not by the B(2) receptor antagonist HOE 140. Similarly, DABK effects were maintained in B(2) receptor knockout mice. The DABK-induced responses involved the release of neuropeptides from C fibers, as capsaicin treatment inhibited the responses. Treatment with the neurokinin (NK)(1) and NK(3) receptor antagonists attenuated the responses, whereas NK(2), calcitonin gene-related peptide, or platelet-activating factor receptor antagonists had no effect. Substance P caused leukocyte recruitment that, similar to DABK, was inhibited by NK(1) and NK(3) receptor blockade. Mast cell depletion using compound 48/80 reduced DABK-induced leukocyte trafficking, and DABK treatment was shown histologically to induce mast cell degranulation. DABK-induced trafficking was inhibited by histamine H(1) receptor blockade. Our findings provide clear evidence that B(1) receptors play an important role in the mediation of leukocyte-endothelial cell interactions in postcapillary venules, leading to leukocyte recruitment during an inflammatory response. This involves activation of C fibers and mast cells, release of substance P and histamine, and stimulation of NK(1), NK(3), and H(1) receptors.
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PMID:Association between kinin B(1) receptor expression and leukocyte trafficking across mouse mesenteric postcapillary venules. 1093 25

Upon activation nociceptors release neuropeptides in the skin provoking vasodilation and plasma protein extravasation in rodents, but only vasodilation in humans. Pivotal peptides in the induction of neurogenic inflammation comprise calcitonin gene-related peptide and substance P, the latter being suggested to act partly via degranulation of mast cells. In this study substance P and calcitonin gene-related peptide-induced vasodilation, protein extravasation, histamine release, and sensory effects were investigated simultaneously in human skin by dermal microdialysis. The vasodilatory prostaglandin E(2) and the mast cell activator codeine served as positive controls. Substance P and calcitonin gene-related peptide applied intradermally via large cut-off plasmapheresis capillaries induced dose-dependent local vasodilation, but only SP provoked protein extravasation in concentrations greater than 10(-9) M. Substance P-induced (10(-8)-10(-6) M) protein extravasation was not accompanied by histamine release and was unaffected by cetirizine (histamine H1 blocker, 200 microg per ml). Only the highest concentration of substance P (10(-5) M) induced significant histamine release. Neither neuropeptide caused any axon reflex erythema or any itch or pain sensation, whereas mast cell degranulation by codeine dose dependently provoked itch, flare, protein extravasation, and histamine release. In human skin calcitonin gene-related peptide and substance P induce vasodilation by a mechanism not involving histamine. No evidence for neuropeptide-induced activation of nociceptors was obtained. Our results suggest that endogenous calcitonin gene-related peptide and substance P have no acute sensory function in human skin. The lack of neurogenic protein extravasation in humans can most probably be attributed to low local concentrations of this neuropeptide still sufficient to exert trophic and immunomodulatory effects (10(-11) M), but too low to induce protein extravasation (10(-8) M) or even mast cell degranulation (10(-5) M). J Invest Dermatol 115:1015-1020 2000
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PMID:Acute effects of substance P and calcitonin gene-related peptide in human skin--a microdialysis study. 1112 Nov 35

Evidence exists to support the concept that ovarian hormones influence mast cell functioning and related events. Here, we evaluated the constitutive gender difference and the influence of ovarian status on rat mast cell (MC) distribution in jejunum and colon, histamine synthesis and/or its release elicited by Substance P (SP). Higher mast cell (MC) number and histamine release were found in female compared with male. In female rats, hormonal status did not affect the density of resident MC neither in the jejunum nor in the colon. Interestingly, histamine levels released after SP stimulation of jejunal segment was reduced in ovariectomized (OVX) compared with sham OVX rats, and restored in OVX female receiving progesterone. In the colon, OVX resulted in a significant increase in histamine levels released after SP stimulation and a treatment with progesterone did not restore basal histamine levels. Thus, ovarian steroid hormones do not affect jejunal and colonic mast cell number. However, the hormonal status differently influences jejunal and colonic MC sensitivity to SP.
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PMID:Effect of ovarian hormones on intestinal mast cell reactivity to substance P. 1121 68

A significant role for the alternative complement pathway in acid aspiration has been demonstrated by the observation that C3 but not C4 genetic knockout mice are protected from permeability edema. Using mast cell-deficient mice (W/Wv), we tested the hypothesis that mast cells mediate complement activation after acid aspiration. Tracheostomy tubes were placed in anesthetized mice and 2 mL/kg 0.1 N HCL was instilled in the trachea. After 4 h, extravasation of 125I-albumin was used to calculate lung vascular permeability. The serum alternative complement pathway hemolytic activity was examined, and lung immunohistochemistry was performed. Lung permeability in W/Wv mice was 62% less than that of mast cell sufficient (+/+) animals and similar to +/+ mice treated with the chymase inhibitor chymostatin (65% decrease). Treatment of +/+ mice with D-PRO2,D-TRP(7,9)-Substance P, an antagonist to the neuropeptide substance P, reduced injury by 66%. Serum complement hemolytic activity was intact in injured w/wv mice and +/+ animals treated with chymostatin or dpdt-sp, but was decreased to 65% in the injured untreated +/+ group. Alveolar C3 deposition was intense in injured untreated +/+ mice but absent in the other groups. We interpret these data to indicate that mast cells mediate complement activation, via chymase degranulation, after acid aspiration. This mast cell activity likely is regulated by the release of substance P.
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PMID:Mast cells mediate complement activation after acid aspiration. 1144 10


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