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)

Schistosome granulomas make substance P (SP). CP96,345 is a nonpeptide SP receptor antagonist active in vivo. Granulomas that form in the presence of SP receptor blockade produce little IgM as compared to normal lesions. The objective of this study was to determine how CP96,345 modulates granuloma IgM production. Schistosome ova were embolized to the lungs of infected mice to induce granulomas of synchronous age. Animals received CP96,345 (50 mg/kg/day) for 4 days following egg embolization. Then granulomas were isolated from tissue and dispersed into single-cell preparations. The dispersed granuloma cells were cultured in vitro to measure IgM and cytokine secretion. Also, granuloma B cells were studied using an IgM ELISPOT assay and flow cytometry. As expected, mice treated with CP96,345 formed granulomas that secreted little IgM. Granulomas from CP96,345-treated mice, as compared to buffer-treated animals, contained few IgM-secreting B lymphocytes, but had appropriate numbers of B cells expressing surface IgM. Also decreased was the capacity of the granulomas to make IFN-gamma, IL-4, IL-5 and IL-6. CP96,345 treatment did not affect splenocyte IgM or cytokine synthesis. These data suggest that CP96,345 inhibits granuloma IgM secretion by blocking intragranuloma B cell maturation at a terminal stage of B cell differentiation. Moreover, SP receptor antagonist affects a variety of cytokine circuits that could influence IgM B cell maturation in vivo.
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PMID:Substance P receptor antagonist inhibits murine IgM expression in developing schistosome granulomas by blocking the terminal differentiation of intragranuloma B cells. 896 2

Polycationic mast cell activators, such as compound 48/80 and substance P, have been reported to activate connective tissue-type mast cells specifically by interacting directly with the Gi family of trimeric GTP-binding protein. We now demonstrate that mouse bone marrow-derived mast cells (BMMC) developed in IL-3, an immature mast cell population lacking responsiveness to the Gi-coupled polycationic mast cell activators, underwent maturation toward a connective tissue-type mast cells-like phenotype that responded to polycationic compounds after only 4 to 6 days of coculture with Swiss 3T3 fibroblasts in concert with recombinant soluble c-kit ligand (KL), whereas 3T3 or KL alone was insufficient to mediate this process. Under optimal conditions, cocultured BMMC released approximately 30% beta-hexosaminidase and generated approximately 1 ng of PGD2/10(6) cells within a few minutes in response to compound 48/80 or substance P. Furthermore, these cells expressed cytokines, such as IL-1beta and IL-6, and PG endoperoxide synthase-2 1 to 4 h after stimulation with compound 48/80 or substance P. All these responses were suppressed effectively by pertussis toxin, implicating functional Gi coupling. Regardless of the remarkable change in polycationic compound sensitivity, there was only a minimal change in the constitutive expression of Gi3 alpha after coculture. These results together with the observation that before coculture BMMC responded to thrombin through its Gi-coupled receptor suggest that the alteration in a certain step(s) distinct from the level of Gi3 alpha protein expression is important for the acquisition of responsiveness to the polycationic compounds by the synergistic action of KL and 3T3 fibroblast-derived factor. Several lines of evidence have revealed that 3T3-derived factor appears to differ from the known cytokines, prostanoids, and adhesion molecules and is a labile soluble substance.
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PMID:Mouse bone marrow-derived mast cells undergo exocytosis, prostanoid generation, and cytokine expression in response to G protein-activating polybasic compounds after coculture with fibroblasts in the presence of c-kit ligand. 897 15

The lung is richly supplied with peptidergic nerves that store and secrete substance P (SP), vasoactive intestinal peptide (VIP), and other neuropeptides known to potently modulate leukocyte function in vitro and airway inflammation in vivo. To investigate and characterize neuromodulation of immune responses compartmentalized in lung parenchyma, neuropeptide release and expression of neuropeptide receptors were studied in lungs of antigen-primed C57BL/6 mice after intratracheal challenge with sheep erythrocytes. The concentrations of cytokines in bronchoalveolar lavage (BAL) fluid rose early and peaked on day 1 for interleukin (IL)-2, interferon gamma, and IL-10; days 1 to 2 for IL-6; and day 3 for IL-4, whereas the total number and different types of leukocytes in BAL fluid peaked subsequently on days 4 to 6 after i.t. antigen challenge. Immunoreactive SP and VIP in BAL fluid increased maximally to nanomolar concentrations on days 1 to 3 and 2 to 7, respectively in lungs undergoing immune responses. The high-affinity SP receptor (NK-1 R), and VIP types I (VIPR1) and II (VIPR2) receptors were localized by immunohistochemistry to surface membranes of mononuclear leukocytes and granulocytes in perivascular, peribronchiolar, and alveolar inflammatory infiltrates during immune responses. As quantified by reverse transcription-polymerase chain reaction, significant increases were observed in levels of BAL lymphocyte mRNA encoding NK-1 R (days 2 to 4), VIPR1 (days 2 to 4), and VIPR2 (days 4 to 6), and in alveolar macrophage mRNA encoding NK-1 R (days 2 to 6) and VIPR1 (days 2 to 4), but not VIPR2. Systemic treatment of mice with a selective, nonpeptide NK-1 R antagonist reduced significantly the total numbers of leukocytes, lymphocytes, and granulocytes retrieved by BAL on day 5 of the pulmonary immune response. The results indicate that SP and VIP are secreted locally during pulmonary immune responses, and are recognized by leukocytes infiltrating lung tissue, and thus their interaction may regulate the recruitment and functions of immune cells in lung parenchyma.
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PMID:Upregulation of neuropeptides and neuropeptide receptors in a murine model of immune inflammation in lung parenchyma. 903 20

The physiological and behavioral disturbances observed during an infection can be reproduced by systemic administration of proinflammatory cytokines (e.g., interleukin (IL)-1, IL-6, tumor necrosis factor-alpha) or lipopolysaccharide (LPS), a potent inducer of these cytokines. It is now well established that these molecules induce their effects by acting centrally, however, the mechanisms by which they reach central structures are not clear. We have earlier proposed that the humoral immune message is converted to a central neural activation by the action of cytokines on peripheral terminations of afferent neurons. Subdiaphragmatic vagotomy abolishes several effects of peripherally injected IL-1beta and LPS (e.g., decreased food-motivated behavior and social exploration, central expression of cytokines). To further define the nature of the peripheral fibers implicated in this phenomenon, we used a potent sensory neurotoxin, capsaicin, to selectively destroy C-fiber afferents. Adult rats were injected I.P. with a total dose of 25 mg/kg capsaicin in a series of 10 injections over a 48-h period. Adult mice were injected I.P. with a total dose of 75 mg/kg in a series of seven injections over a 7-day period. Although capsaicin treatment altered visceral chemosensory function, corneal and pain sensitivity, vagal-mediated anorexic effects of cholecystokinin, and depleted levels of substance P in the thoracic spinal cord, it was completely ineffective in blocking the decrease in food-motivated behavior induced by IL-1beta (4 microg/rat I.P. in rats) and LPS (250 microg/kg I.P. in rats and 400 microg/kg I.P. in mice). Thus, other afferents besides capsaicin-sensitive C-fibers appear to be involved in the transduction of cytokine effects during inflammatory and infectious events.
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PMID:Systemic capsaicin pretreatment fails to block the decrease in food-motivated behavior induced by lipopolysaccharide and interleukin-1beta. 912 19

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

In human astrocytoma cell lines, substance P (SP) stimulated interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor and leukemia inhibitory factor protein secretion. These SP effects were blocked by a specific NK1 tachykinin receptor antagonist. Further, SP stimulation increased the half-life of IL-6 and IL-8 messenger RNAs, suggesting that the synthesis of these cytokines is also regulated post-transcriptionally. SP-induced cytokine release was inhibited by staurosporine and phorbol 12-myristate 13-acetate desensitization suggesting protein kinase C involvement. The demonstration that SP affects cytokine production in glioma cells might be of relevance for the biology of such tumors.
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PMID:Substance P induces secretion of immunomodulatory cytokines by human astrocytoma cells. 952 14

The inhibitory effect of inflammation and endotoxins on the secretion of reproductive hormones from the hypothalamo-pituitary axis is well documented. A comparison of the luteinizing hormone (LH) suppressing effects of several pro-inflammatory cytokines revealed that centrally administered IL-1 beta was the most potent inhibitor of pituitary LH secretion; interleukin (IL)-1 alpha and tumor necrosis factor (TNF) alpha were relatively less effective, whereas IL-6 was ineffective. This order of potency suggested that the anti-gonadotropic effects of an immune challenge are most likely attributable to the action of centrally released IL-1 beta, and this was supported by the demonstration that IL-1 beta suppressed hypothalamic luteinizing hormone releasing hormone (LHRH) release. We used a multifaceted approach to identify the afferent signals in the brain that convey immune messages to hypothalamic LHRH neurons. Pharmacological studies with specific antagonists of opioid receptor subtypes demonstrated that activation of the mu 1 receptor subtype was required to transmit the cytokine signal. Furthermore, icv IL-1 beta upregulated hypothalamic POMC mRNA and increased the concentration and release of beta-endorphin, the primary ligand of mu 1 receptors. We have obtained evidence that IL-1 beta also enhanced the gene expression and concentration of tachykinins, a family of nociceptive neuropeptides in the hypothalamus. Blockade of tachykinergic NK2 receptors attenuated IL-1 beta induced inhibition of LH secretion. Collectively, these results demonstrate that IL-1 beta, generated centrally in response to inflammation, upregulates the opioid and tachykinin peptides in the hypothalamus. These two groups of neuropeptides are critically involved in relaying the cytokine signal to neuroendocrine neurons and causing the suppression of hypothalamic LHRH and pituitary LH release.
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PMID:The anti-gonadotropic effects of cytokines: the role of neuropeptides. 978 36

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

Recent experiments have shown that human bronchial epithelial cells (i.e., BEAS-2B) release pro-inflammatory cytokines (i.e., IL-6 and TNFalpha) in a receptor-mediated fashion in response to the neuropeptides, substance P (SP), calcitonin gene-related protein (CGRP), and the prototype botanical irritant capsaicin. In the present experiments, we examined the relevance of these receptors to particulate matter (PM)-associated cellular inflammation. BEAS-2B cells, exposed to residual oil fly ash particles (ROFA), responded with an immediate (<30 s) increase in intracellular calcium levels ([Ca2+]i), increases of key inflammatory cytokine transcripts (i.e., IL-6, IL-8, TNFalpha) within 2 h exposure, and subsequent release of IL-6 and IL-8 cytokine protein after 4 h exposure. Pretreatment of BEAS-2B cells with pharmacological antagonists selective for the SP or CGRP receptors reduced the ROFA-stimulated IL-6 cytokine production by approximately 25 and 50%, respectively. However, pretreatment of these cells with capsazepine (CPZ), an antagonist for capsaicin (i.e., vanilloid) receptors, inhibited the immediate increases in [Ca2+]i, diminished transcript (i.e., IL-6, IL-8, TNFalpha) levels and reduced IL-6 cytokine release to control levels. BEAS-2B cells exposed to ROFA in calcium-free media failed to demonstrate increases of [Ca2+]i and showed reduced levels of cytokine transcript (i.e., IL-6, IL-8, TNFalpha) and IL-6 release, suggesting that ROFA-stimulated cytokine formation was partially dependent on extracellular calcium sources. A final set of experiments compared the inflammatory properties of the soluble and acidic insoluble components of ROFA. BEAS-2B cells, exposed to ROFA or ROFA that had been filtered through a 0.2-micrometer pore filter, produced equivocal IL-6. BEAS-2B cells exposed to pH 5.0 media for 15 min released moderate amounts of IL-6, 4 h later. This cytokine release could be blocked by amiloride, a pH receptor antagonist, but not by CPZ. BEAS-2B cells, pretreated with amiloride before ROFA exposure, showed a partial (approximately 25%) reduction of IL-6. Together, these data indicate that the acidic, soluble components of ROFA initiate cytokine release in BEAS-2B cells through activation of both capsaicin- and pH-sensitive irritant receptors.
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PMID:Particulate matter initiates inflammatory cytokine release by activation of capsaicin and acid receptors in a human bronchial epithelial cell line. 988 97

Inflammatory mediators play a key role in acute pancreatitis and the resultant multiple organ dysfunction syndrome, which is the primary cause of death in this condition. Recent studies have confirmed the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, PAF, IL-10, C5a, ICAM-1, and substance P. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicaemia, severe burns, and trauma. The delay between the onset of inflammation in the pancreas and the development of the systemic response makes acute pancreatitis an ideal experimental and clinical model with which to study the role of inflammatory mediators and to test novel therapies. Elucidation of the key mediators involved in the pathogenesis of acute pancreatitis will facilitate the development of clinically effective anti-inflammatory therapy.
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PMID:Inflammatory mediators in acute pancreatitis. 1065 8


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