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)

The health effect of atmospheric pollution is causing increasing public concern. Several controlled human-exposure studies have clearly. shown that oxidant pollutants, including ozone, nitrogen dioxide, and diesel exhaust, induce an acute inflammatory response in human airways. The main component of this response involves the influx of polymorphonuclear leukocytes (PMN) and is mediated via the upregulation of transcription factors NF-kappa B, AP-1, and NF-IL6; leukocyte-endothelial adhesion molecules, and chemokine secretion, including IL-8 and Gro-alpha. The results of recent studies also suggest that short-term exposure to ozone leads to neurogenic inflammation by causing damage to the bronchial epithelium and stimulating subepithelial sensory nerves to release substance P. In addition, such exposures lead to the consumption of endogenous antioxidants that are present in the airway lining fluid. Studies in asthmatics have shown that oxidant pollutants, including ozone and nitrogen dioxide, induce PMN influx in the airways and potentiate responses to inhaled aero-allergens. This article will review various studies addressing the toxicological mechanisms underlying oxidant pollutant-induced airways injury.
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PMID:Toxicological mechanisms underlying oxidant pollutant-induced airway injury. 971 22

Ultraviolet (UV) irradiation of the skin causes both inflammation and alterations in the skin immune system. There is increasing experimental evidence that UV-induced skin inflammation is influenced by the sensory nervous system and the neuroendocrine system in the skin. The resulting complex network of cytokines, chemokines, neuropeptides, neuropeptide-degrading enzymes, neurohormones, and other inflammatory mediators mediate photodermatitis and cutaneous inflammation. Neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) are released from sensory nerves innervating the skin upon UV exposure. In addition, a variety of cells in the skin produce increased neuroendocrine hormones such as proopiomelanocortin (POMC) peptides and their receptors as well as neurotrophins after UV exposure. Neuropeptides and neurohormones are capable of directly or indirectly mediating UV-induced cutaneous neurogenic inflammation by the induction of vasodilatation, plasma extravasation, and augmentation of UV-induced cytokine, chemokine, or cellular adhesion molecule expression required for activation and trafficking of inflammatory cells into the inflamed tissue. Neuropeptides and neurotrophins may also play a role in the repair of cutaneous UV injury. In addition to proinflammatory effects, UV-induced neuropeptides and neurohormones such as CGRP and alpha-melanocyte-stimulating hormone may have immunosuppressive effects in the skin. This review will focus on the role that SP, CGRP, POMC peptides, and their receptors may play in modulating UV-induced inflammation in the skin.
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PMID:Effect of ultraviolet light on the release of neuropeptides and neuroendocrine hormones in the skin: mediators of photodermatitis and cutaneous inflammation. 1053 9

Elevated extracellular K(+) ([K(+)](o)), in the absence of "classical" immunological stimulatory signals, was found to itself be a sufficient stimulus to activate T cell beta1 integrin moieties, and to induce integrin-mediated adhesion and migration. Gating of T cell voltage-gated K(+) channels (Kv1.3) appears to be the crucial "decision-making" step, through which various physiological factors, including elevated [K(+)](o) levels, affect the T cell beta1 integrin function: opening of the channel leads to function, whereas its blockage prevents it. In support of this notion, we found that the proadhesive effects of the chemokine macrophage-inflammatory protein 1beta, the neuropeptide calcitonin gene-related peptide (CGRP), as well as elevated [K(+)](o) levels, are blocked by specific Kv1.3 channel blockers, and that the unique physiological ability of substance P to inhibit T cell adhesion correlates with Kv1.3 inhibition. Interestingly, the Kv1.3 channels and the beta1 integrins coimmunoprecipitate, suggesting that their physical association underlies their functional cooperation on the T cell surface. This study shows that T cells can be activated and driven to integrin function by a pathway that does not involve any of its specific receptors (i.e., by elevated [K(+)](o)). In addition, our results suggest that undesired T cell integrin function in a series of pathological conditions can be arrested by molecules that block the Kv1.3 channels.
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PMID:Extracellular K(+) and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and beta1 integrins. 1074 34

Membrane peptidases are a group of ectoenzymes with a broad functional repertoire. In protein metabolism, their importance is well known, especially in peptide degradation and amino acid scavenging at the intestinal and renal brush border. However, they also perform more subtle tasks; not only do they provide or extinguish signals by cleaving exterior peptide mediators, but they also may function as receptors or participate in signal transduction or in adhesion. Dipeptidyl peptidase IV (DPPIV), which is identical to the lymphocyte surface glycoprotein CD26, is unique among these peptidases because of its ability to liberate Xaa-Pro and less efficiently Xaa-Ala dipeptides from the N-terminus of regulatory peptides. It occurs in the plasma membrane as a homodimer with a total molecular mass of 22-240 KdA and the C-terminal domain probably forms on alpha/beta hydrolase fold. In addition to, but independent of its serine type catalytic activity, DPPIV binds closely to the soluble extracellular enzyme adenosine deaminase. The in vivo expression on epithelial, endothelial and lymphoid cells of DPPIV is compatible with a role as physiological regulator of a number of peptides that serve as biochemical reporters between and within the immune and neuroendocrine system. Surprisingly, not cytokines with a N-terminal Xaa-Pro motif, but a number of chemokines have recently been identified as substrates. Despite DPPIV mediates only a minimal N-terminal truncation, important alterations in chemokine activities and receptor specificitIes were observed in vitro together with modified inflammatory and antiviral responses. Most probably the great flexibility of the N-terminus of a number of chemokines facilitates the accessibIlity to the catalytic site of DPPIV. Other known substrates which are subject in vitro to receptor-specific changes induced by DPPIV truncation include neuropeptides such as substance P, peptidE YY and neuropeptide Y. On the other hand, DPPIV mediated cleavage of the N-terminal His-Ala or Tyr-Ala dipeptides from circulating incretin hormones like, glucagon-like peptides (GLP)-1 and -2, gastric inhibitory polypeptide (GIP), all members of the enteroglucagon/GRF superfamily, results in their biological inactivation in vitro and in vivo. Administration of specific DPPIV inhibitors closes this pathway of incretin degradation and greatly enhances insulin secretion. The improved glucose tolerance in several animal models for type II diabetes points to specific DPPIV inhibition as a pharmaceutical approach for type 2 diabetes drug development.
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PMID:Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery? 1128 88

The neurokinin (NK) substance P (SP), which is a mediator of neurogenic inflammation, has been reported to prime human polymorphonuclear neutrophils (PMNs). The priming effects of SP on PMNs activated by recombinant interleukin-8 (rIL-8) were investigated. SP enhanced, in a dose- and time-dependent way, the rise in cytosolic free-calcium concentration, [Ca(2+)]i, evoked by the chemokine. The priming effects of SP were abolished by exposing PMNs to a calcium-free medium supplemented with EGTA. The C-terminal peptides SP(4-11) and SP(6-11) but not the N-terminal peptide SP(1-7) shared the priming effects of SP. The selective NK-1 receptor agonist [Sar-9, MetO2-11]SP mimicked the effects of SP, which were not reproduced by the selective NK-2 receptor agonist [betaAla-8]-NKA(4-10) or the selective NK-3 agonist senktide. Two selective NK-1 antagonists, CP96,345 and L703,606, dose dependently inhibited SP priming effects. These results demonstrated that SP primes PMNs exposed to rIL-8 and suggested that SP priming effects are receptor mediated.
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PMID:Priming effects of substance P on calcium changes evoked by interleukin-8 in human neutrophils. 1140 89

Human immunodeficiency virus-1 (HIV-1) infection is associated with numerous effects on the nervous system, including pain and peripheral neuropathies. We now demonstrate that cultured rat dorsal root ganglion (DRG) neurons express a wide variety of chemokine receptors, including those that are thought to act as receptors for the HIV-1 coat protein glycoprotein120 (gp120). Chemokines that activate all of the known chemokine receptors increased [Ca(2+)](i) in subsets of cultured DRG cells. Many neurons responded to multiple chemokines and also to bradykinin, ATP, and capsaicin. Immunohistochemical studies demonstrated the expression of the CXCR4 and CCR4 chemokine receptors on populations of DRG neurons that also expressed substance P and the VR1 vanilloid receptor. RT-PCR analysis confirmed the expression of CXCR4, CX3CR1, CCR4, and CCR5 mRNAs in DRG neurons. Chemokines and gp120 produced excitatory effects on DRG neurons and also stimulated the release of substance P. Chemokines and gp120 also produced allodynia after injection into the rat paw. Thus these results provide evidence that chemokines and gp120 may produce painful effects via direct actions on chemokine receptors expressed by nociceptive neurons. Chemokine receptor antagonists may be important therapeutic interventions in the pain that is associated with HIV-1 infection and inflammation.
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PMID:Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. 1143 78

Genetically manipulated mice exhibiting altered innervation of the airways were used to examine the role of sensory nerves in ozone-induced lung inflammation. Transgenic mice expressing nerve growth factor (NGF) from the lung-specific Clara cell secretory protein (CCSP) promoter exhibit hyperinnervation of the airways by sympathetic and tachykinin-containing sensory nerve fibers. Mice carrying a mutation in the low-affinity NGF receptor (NGFR) gene possess deficits in sensory innervation. CCSP-NGF transgenic mice exhibited a twofold increase in the number of lung lavage neutrophil level whereas NGFR knockout mice exhibited a nearly 50% decrease in neutrophilic inflammation compared with wild-type mice 18 h after ozone inhalation. Treatment with neurokinin receptor antagonists reduced the level of neutrophilic inflammation in both wild-type and CCSP-NGF mice. Examination of lavage fluid cytokine concentrations revealed that 4 h after ozone exposure CCSP-NGF mice produced significantly higher amounts of the chemokine KC than wild-type mice exposed to ozone. The results of this study indicate that sensory nerves are important mediators of ozone-induced inflammation in mice.
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PMID:Sensory nerves promote ozone-induced lung inflammation in mice. 1146 6

Substance P (SP), a potent modulator of neuroimmunoregulation, exerts its activity by binding to the neurokinin-1 receptor (NK-1R). The SP-NK-1R interaction is important in inflammation and viral infections, including HIV infection of human immune cells. We recently demonstrated that SP modulates HIV replication and that a non-peptide SP antagonist CP-96,345 inhibits HIV replication in human monocyte-derived macrophages (MDM) by affecting the SP-NK-1R interaction. In order to examine the effect of the SP antagonist on SP mRNA expression, MDM was incubated with or without CP-96,345 in the presence or absence of HIV infection. SP mRNA expression in these cells was then determined by real-time PCR technology. The effect of CP-96,345 on chemokine gene expression was also investigated by using a cDNA array assay. CP-96,345 down-regulated SP mRNA expression and antagonized exogenous SP-enhanced SP expression at the mRNA level, suggesting that SP autocrine regulation was interrupted by CP-96,345. CP-96,345 inhibited HIV replication in MDM, associated with down-regulated SP mRNA expression in comparison to HIV infection controls. In parallel with down-regulated SP and CCR5 mRNA expression, cDNA array assays indicated that CP-96,345 treatment also inhibited IL-8 gene expression, while enhancing expression of fractalkine and monocyte chemotactic protein-3 (MCP-3). Since SP plays an important role in inflammation and viral infections, these studies may have potential applications for therapeutic intervention of inflammation and viral infection of immune cells.
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PMID:A non-peptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes. 1209 17

Substance P (SP) is an important modulator of neuroimmunoregulation. We have demonstrated that human T lymphocytes express SP and neurokinin-1 receptor (NK-1R), a primary SP receptor. In the present study, we investigated whether SP stimulates synthesis of macrophage inflammatory protein-1beta (MIP-1beta) in human T lymphocytes. SP significantly enhanced MIP-1beta expression at both the mRNA and protein level in a human T cell line (Jurkat) containing the SP receptor gene (J-SPR) as determined by real-time PCR and ELISA assays. SP-induced MIP-1beta expression is abrogated by the specific NK-1R antagonist (CP-96,345). The supernatants from SP-stimulated J-SPR T cell cultures enhanced T lymphocyte chemotaxis in vitro, indicating functional activity of SP-induced MIP-1beta. In addition, SP augmented secretion of MIP-1beta from primary cultures of peripheral blood lymphocytes (PBL) isolated from some of the donors. This donor variability was due to differential expression of the primary SP receptor (NK-1R) on PBL from different donors. PBL from two of seven donors that did not respond to SP stimulation had undetectable NK-1R expression. Our mechanistic studies showed that SP activated NF-kappaB promoter-directed luciferase activity, which may be responsible for its effect on MIP-1beta expression in human T cells. Our data provide a potential mechanism by which SP selectively influences cellular immune responses such as beta-chemokine expression in human T lymphocytes through NK-1R, which may have an important in vivo implication in inflammatory diseases.
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PMID:Substance P up-regulates macrophage inflammatory protein-1beta expression in human T lymphocytes. 1245 47

Preprotachykinin-A (PPT-A) gene-derived neuropeptides, namely substance P (SP) and neurokinin (NK)A, and their receptors participate in allergen-induced airway responses. Whether airway smooth muscle cells (ASMC) may react directly to SP through expression of the NK-1 receptor or express the gene for the synthesis of SP, the PPT-A gene, is unknown. We demonstrated using reverse transcription-polymerase chain reaction that tracheal SMC (TSMC) from atopic Brown Norway rats contained mRNA transcripts for the full-length isoform of the NK-1 receptor. Flow cytometric analysis indicated that the NK-1 receptor was expressed on the surface of TSMC. This receptor was functional as demonstrated by calcium mobilization in response to SP stimulation. The expression of the NK-1 receptor was not altered in passively sensitized TSMC in response to antigenic stimulation, although this stimulation increased the expression of the chemokine RANTES (regulated on activation, normal T cells expressed and secreted). Using different sets of PCR primers, we showed that TSMC also express the beta, alpha, and its alternative splicing product delta, and possibly the gamma mRNA transcript isoforms of the PPT-A gene. Gene sequencing of the PCR-amplified beta isoform confirmed that it is a transcript product of the rat PPT-A gene, and the production of SP by TSMC was confirmed by enzyme immunoassay. We also showed the beta isoform increased after cell stimulation with rat sera, whether sensitized or not. In conclusion, both the PPT-A gene and NK-1 receptors are expressed by TSMC, which suggests the possibility of autocrine neuropeptidergic mechanisms in these cells. However, these mechanisms are not upregulated by passive sensitization.
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PMID:Airway smooth muscle cells express functional neurokinin-1 receptors and the nerve-derived preprotachykinin-a gene: regulation by passive sensitization. 1249 38


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