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)

We have been studying hematopoietic effects by the tachykinins, which like many other neuropeptides can be expressed in neural and nonneural tissues. Substance P (SP) and neurokinin-A (NK-A), members of the tachykinins are immune and hematopoietic modulators. SP and NK-A are derived from the preprotachykinin-I gene (PPT-I) through alternate splicing and posttranslational modification. In the bone marrow (BM), nerve fibers provide a source of neural SP and the stroma provides a source of nonneural SP. The tachykinins interact with each of three cloned neurokinin (NK) receptors (NK-1R, NK-2R, NK-3R) with SP and NK-A exhibiting binding preferences for NK-1R and NK-2R, respectively. Proliferation of myeloid progenitors (CFU-GM) is differentially regulated by SP and NK-A. The former enhances the proliferation whereas the latter is inhibitory. The BM stroma mediates most of the hematopoietic effects exerted by SP and NK-A partly through the induction of cytokines. The proliferative effects of SP correlate with the induction of positive hematopoietic growth factors such as IL-3, IL-6, GM-CSF and c-kit ligand and the inhibitory effects by NK-A correlate with the induction of two negative hematopoietic regulators, MIP-1 alpha and TGF-beta. Intracellular signals mediated by NK-1R and NK-2R are part of the mechanism responsible for tachykinin-mediated regulation of hematopoiesis. The stimulatory effects on BM progenitors mediated by NK-1R can be partly inhibited by NK-2R activation. IL-1 and other cytokines induced by SP in BM stroma modulate NK-1R induction. Furthermore, SP can induce IL-1 type I receptor in stroma. Together, these data suggest that the tachykinins and the cytokines interact to regulate hematopoiesis. These interactions contribute to hematopoietic regulation by mechanisms that involve induction of: (1) tachykinins and cytokines by each other; (2) NK-1R by cytokines and (3) cytokine receptor by the tachykinins. These studies emphasize that in terms of hematopoiesis, the cytokines and neuropeptides are not mutually exclusive factors and thus, the hematopoietic regulatory network would be incomplete without the role of neuropeptides being considered.
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PMID:Hematopoietic modulation by the tachykinins. 928

Sodium-butyrate-pretreated and Con A-stimulated P815 mast cell line generated 3T3 fibroblast proliferating activity. This fibroblast stimulatory activity was partially abrogated by three different substance P antagonists such as spantide (NK1 antagonist), FK224 (NK1 and NK2 antagonist) or FK888 (NK1 antagonist) or anti-substance P antibody. In addition to P815 mastocytoma cell, IL3-dependent, bone marrow-derived mast cells also generated fibroblast proliferating activity which was also partially abrogated by substance P antagonists. Anti-fibrogenic cytokine antibodies also inhibited mast cell-derived fibroblast proliferating activity. Substance P or histamine augmented fibrogenic cytokine-induced fibroblast proliferation which indicates that mast cell-derived histamine or substance P play an important role in induction of tissue fibrosis in fibrosing diseases.
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PMID:Substance P augments fibrogenic cytokine-induced fibroblast proliferation: possible involvement of neuropeptide in tissue fibrosis. 930 48

Substance P (SP) is a neuropeptide widely distributed in the nervous system. Extensive study has shown SP stimulates production of various cytokines by bone marrow stromal cells, although, the role of SP in hematopoietic phenomena is still unclear. Recently, we established a human cloned stromal cell line, HAS303, which can support hematopoietic stem cell proliferation and differentiation in vitro. We used this culture system to examine the effects of SP. Expression of the mRNAs of neurokinin (NK)-1R, NK-2R and NK-3R, specific SP receptors, on HAS303 cells was demonstrated by the RT-PCR. CD34+ cells isolated from bone marrow were co-cultivated with HAS303 cells in the presence and absence of SP and the total hematopoietic cells and progenitors were counted every 5 days. Introducing SP (10(-8) M) to the co-cultures significantly increased the number of total cells and progenitors compared with control cultures. SP showed no enhancing activity on CD34+ cells cultured alone. SP also stimulated IL-3-dependent colony formation of whole bone marrow MNCs in a soft agar culture system, but showed no such activity on isolated CD34+ cells in this system. These observations suggest that SP stimulated HAS303 cells, activated HAS303 cells, and stimulated the proliferation and differentiation of CD34+ cells. Treating HAS303 cells with SP increased the intracellular Ca2+ concentration and stimulated production of G-CSF, GM-CSF, SCF and IL-6, but not IL-1alpha, IL-1beta and TNF-alpha, but did not enhance proliferation. All these findings suggest that SP mediates hematopoietic cell proliferation and differentiation in vitro by activating stromal cell function.
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PMID:Stimulatory effects of substance P on CD34 positive cell proliferation and differentiation in vitro are mediated by the modulation of stromal cell function. 985 36

The response of mast cells (MC) to non-IgE-mediated stimulation is critically dependent on the population of MC examined. The neuropeptide Substance P (SP) has been reported to activate connective tissue-type MC (CTMC), while mucosal MC (MMC) are not activated by SP. We examined the effect of stem cell factor (SCF) plus interleukin-4 (IL-4) on SP-initiated activation of bone marrow-derived MC (BMMC). Mouse MC, derived from a culture of BM cells with IL-3, were subsequently treated with recombinant SCF plus IL-4 for 6 days. Responsiveness to SP was monitored measuring beta-hexosaminidase and lipid mediator release. Histochemical staining, histamine analysis, and granule protease expression were achieved to characterize the cells. In contrast to IL-3 grown cells, SCF/IL-4-exposed cells showed functional responsiveness to release beta-hexosaminidase (42.25% +/- 1.46% at SP concentration of 100 microM) and produce leukotriene C(4) (LTC(4)) (7.4 +/- 1.5 ng/10(6) cells)/prostaglandin D(2) (PGD(2)) (2.0 +/- 0.3 ng/10(6) cells) upon stimulation by SP. The increase in sensitivity of the cells to SP was not due to differentiation into CTMC, as the cells remained heparin negative. Both SCF and IL-4 were needed because SCF or IL-4 alone were insufficient to keep cells viable after 3 to 4 days post coculture. SP-induced secretion from BMMC cultured in medium containing SCF plus IL-4 (25.76% +/- 1.83%) was higher in comparison with cells cultured with SCF plus IL-3 (8.85% +/- 0.68%).These findings indicate that temporal changes in cytokine expression can influence the sensitivity of MC to non-immunologic stimuli. Local cytokine production leading to an increase in MC responsiveness to SP and inducing secretion of granule content and lipid generation may, therefore, propagate and worsen inflammatory conditions.
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PMID:Stem cell factor and interleukin-4 increase responsiveness of mast cells to substance P. 1088 Jul 48

Several leukocyte populations normally reside in mouse skin, including Langerhans cells and gammadelta T cells in the epidermis and macrophage and mast cells in the dermis. Interestingly, these skin resident leukocytes are frequently identified within or around hair follicles (HFs), which are known to contain stem cell populations that can generate the epidermal architecture or give rise to the melanocyte lineage. Thus, we reasoned that HFs might serve as a local reservoir of the resident leukocyte populations in the skin. When vibrissal follicles of adult mice were cultured in the presence of stem cell factor (SCF), interleukin 3 (IL-3), IL-7, granulocyte-macrophage colony-stimulating factor, and Flt3 ligand, CD45+/lineage-/c-kit+/FcepsilonRI+ cells became detectable on the outgrowing fibroblasts in 10 days and expanded progressively thereafter. These HF-derived leukocytes showed characteristic features of connective tissue-type mast cells, including proliferative responsiveness to SCF, metachromatic granules, mRNA expression for mast cell proteases-1, -4, -5, and -6, and histamine release on ligation of surface IgE or stimulation with substance P or compound 48/80. These results, together with our findings that HFs contain c-kit+ cells and produce SCF mRNA and protein, suggest that HFs provide a unique microenvironment for local development of mast cells.
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PMID:Hair follicles serve as local reservoirs of skin mast cell precursors. 1273 61

Neurokinin (NK)-1 and NK-2 receptors regulate hematopoiesis by interacting with neurotransmitters that belong to the tachykinin. This report studies the relationship between NK-1 and NK-2 in primary human bone marrow (BM) stroma, which supports hematopoiesis. Use of NK receptor antagonists and deficient stromal cells indicate that the neurotransmitter, substance P (SP), could exert dual hematopoietic effects (inhibitory or stimulatory), depending on the interacting receptor and crosstalk between NK-1 and NK-2. Cloning and identification of the minimal promoter for NK-2 and comparison with NK-1 promoter showed that the hematopoietic functions of NK receptors involve receptor crosstalk and the particular cytokine (IL-3, GM-CSF, TGF-beta or IL-1alpha). Crosstalk between NK-1 and NK-2 adds to communication within neural-hematopoietic axis.
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PMID:Crosstalk between neurokinin receptors is relevant to hematopoietic regulation: cloning and characterization of neurokinin-2 promoter. 1274 55

Vernal keratoconjunctivitis (VKC) is an allergic eye disease that especially affects young boys. The most common symptoms are itching, photophobia, burning, and tearing. The most common signs are giant papillae, superficial keratitis, and conjunctival hyperaemia. Patients with VKC frequently have a family or medical history of atopic diseases, such as asthma, rhinitis, and eczema. However, VKC is not associated with a positive skin test or RAST in 42-47% of patients, confirming that it is not solely an IgE-mediated disease. On the basis of challenge studies as well as immunohistochemical and mediator studies, a Th2-driven mechanism with the involvement of mast cells, eosinophils, and lymphocytes has been suggested. Th2 lymphocytes are responsible for both hyperproduction of IgE (interleukin 4, IL-4) and for differentiation and activation of mast cells (IL-3) and eosinophils (IL-5). Other studies have demonstrated the involvement of neural factors such as substance P and NGF in the pathogenesis of VKC, and the overexpression of oestrogen and progesterone receptors in the conjunctiva of VKC patients has introduced the possible involvement of sex hormones. Thus, the pathogenesis of VKC is probably multifactorial, with the interaction of the immune, nervous, and endocrine systems. The clinical management of VKC requires a swift diagnosis, correct therapy, and evaluation of the prognosis. The diagnosis is generally based on the signs and symptoms of the disease, but in difficult cases can be aided by conjunctival scraping, demonstrating the presence of infiltrating eosinophils. Therapeutic options are many, in most cases topical, and should be chosen on the basis of the severity of the disease. The most effective drugs, steroids, should however be carefully administered, and only for brief periods, to avoid secondary development of glaucoma.A 2% solution of cyclosporine in olive oil or in castor oil should be considered as an alternative. The long-term prognosis of patients is generally good; however 6% of patients develop corneal damage, cataract, or glaucoma.
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PMID:Vernal keratoconjunctivitis. 1506 27

Topical glucocorticoid (GC) is commonly applied in atopic dermatitis treatment. However, the chronic use of GC may be associated with significant side effects. In this study, we investigated whether long-term epicutaneous application of GC modulates scratching behaviour in dinitrofluorobenzene (DNFB) contact-sensitized mice. After challenge with DNFB, scratching behaviour was increased in DNFB-sensitized mice treated with GC in contrast to control mice. In addition, reverse transcriptase-polymerase chain reaction analysis demonstrated that the expression of preprotachykinin-A (PPT-A) mRNA, a precursor of substance P (SP), and inducible nitric oxide synthase (iNOS) mRNA in mice, to which GC was applied, was only observed. In order to evaluate the factors responsible for the augmented scratching behaviour, we injected various cytokines (interleukin-1alpha (IL-1alpha), IL-2, IL-3 and tumour necrosis factor-alpha (TNF-alpha)) subcutaneously into the ear of DNFB contact-sensitized mice before DNFB challenge. Among the cytokines, only IL-3 and TNF-alpha significantly increased scratching behaviour in DNFB contact dermatitis mice. Furthermore, PPT-A mRNA was only expressed in mice pre-injected with IL-3 before challenge, but not in those pre-injected with other cytokines. Taken together, our results suggest that topical GC may augment the itching sensation in DNFB-sensitized mice through modulation of iNOS and SP induced by IL-3.
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PMID:Topical glucocorticoid augments scratching behaviour in dinitrofluorobenzene-sensitized mice by the induction of substance P. 1556 Jul 62

Mast cells are important effector cells of allergy and techniques for culturing human mast cells have been developed in recent years. In the current investigation, we studied the phenotypic and functional characteristics of mast cells cultured from adult human peripheral blood mononuclear cells. Mature human mast cells were obtained by first culturing mononuclear cells in methylcellulose containing stem cell factor (SCF), IL-3 and IL-6 for six weeks and subsequently in liquid medium containing SCF and IL-6 for another six weeks. These cells expressed numerous basophilic cytoplasmic granules that were predominantly tryptase positive but chymase negative. Following sensitization with human IgE, these cells released histamine and synthesized prostaglandin D2 and cysteinyl-leukotrienes dose-dependently upon activation by anti-IgE and calcium ionophores. Compound 48/80 and substance P were ineffective. When the effects of anti-asthmatic agents on anti-IgE induced mediator release from these cells were compared, only the beta2-adrenoceptor agonists and phosphodiesterase inhibitors produced dose-dependent inhibition but not cromolyn. In total, mast cells cultured from human peripheral blood shared similar morphological, immunocytochemical and functional properties of enzymatically dispersed human lung mast cells. These cultured mast cells can be a convenient substitute for the in vitro studies of human lung mast cell reactions and may be useful for investigating the roles of mast cells in allergic diseases.
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PMID:Functional characterization of human mast cells cultured from adult peripheral blood. 1654 15

Mast cells are unique immune cells that release a spectrum of chemical mediators contributing to the inflammatory symptoms of allergic disorders. Although mast cell biology has been extensively studied in the rodents, research on human mast cells is hampered by the lack of a convenient preparation source. This problem has now been addressed by culturing human mast cells from CD34(+) progenitors. We have recently discovered that human buffy coat preparations from local blood banks are an abundant and convenient source of progenitors for culturing mature mast cells which express functional high affinity IgE receptors and contain histamine and tryptase in their granules. In the current study, we further characterize these buffy coat-derived mast cells by studying their responses to common mast cell secretagogues and stabilizers. Mature human mast cells were obtained by culturing isolated progenitors in methylcellulose containing stem cell factor (SCF), IL-3 and IL-6 for 6 weeks and subsequently in liquid medium containing SCF and IL-6 for another 6 to 8 weeks. Following sensitisation with human IgE, these cells released histamine dose-dependently upon activation by anti-IgE and calcium ionophores while compound 48/80 and substance P were relatively ineffective. When the effects of anti-asthmatic agents on anti-IgE-induced mediator release from these cells were compared, only the beta(2)-adrenoceptor agonists and phosphodiesterase inhibitors produced dose-dependent inhibition but not cromolyn or nedocromil. In total, mast cells cultured from human buffy coat progenitors shared similar functional properties of MC(T) subtype of mast cells found predominantly in human lung parenchyma and intestinal mucosa.
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PMID:Histamine release from human buffy coat-derived mast cells. 1732 78


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