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)

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

Following brain injury, astrocytes express receptors for cytokines and neuropeptides and secrete several regulatory mediators that have a well established role in inflammation, immunity, and tissue development or repair. To elucidate the role of substance P (SP), a neurotransmitter peptide of the tachykinin family, in inducing astrocyte secretory activities, we have examined the expression of SP receptors and the functional consequences of their activation in cultured astrocytes from the human embryonic brain or spinal cord. Radioligand binding studies revealed that only one type of SP receptors, the high affinity NK-1 receptor, was present on human astrocytes and that spinal cord astrocytes expressed about 6 times as many SP binding sites as brain astrocytes. Following SP treatment, a substantial inositol phosphate formation was observed in spinal cord astrocytes only. Stimulation of spinal cord astrocytes with SP alone did not induce secretion of cytokines [interleukin-6 (IL-6), granulocyte-macrophage-CSF, macrophage chemoattractant protein-1 or leukemia inhibitory factor] or prostaglandin E2 (PGE2). Interestingly, however, SP selectively potentiated the inducing effect of IL-1beta on IL-6 and PGE2 secretion by spinal cord astrocytes without affecting the IL-1-beta-evoked secretion of other cytokines. SP also enhanced the small inducing effect of tumor necrosis factor-alpha (TNF-alpha) on IL-6 and PGE2 secretion and that of transforming growth factor-beta on PGE2 secretion. These results suggest that SP can enhance immunoregulatory and neurotrophic astroglial functions mediated by IL-6 and PGE2 by acting in concert with a set of cytokines whose cerebral expression has been reported during development and in a variety of diseases.
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PMID:Functional characterization of substance P receptors on cultured human spinal cord astrocytes: synergism of substance P with cytokines in inducing interleukin-6 and prostaglandin E2 production. 933 33

There is increasing experimental evidence that the neurologic system can directly participate in cutaneous inflammation and wound healing. Recent studies indicate that neuropeptides released by cutaneous nerves such as c-fibers can activate a number of target cells including keratinocytes, Langerhans cells, mast cells, and endothelial cells. One such neuropeptide, substance P (SP), is able to specifically bind to murine and human keratinocytes and induce the release of cytokines such as interleukin 1 (IL-1). Other studies demonstrate that SP can also activate mast cells to produce the potent pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha). More recently, we examined the effect of cutaneous neuropeptides on human dermal microvascular endothelial cell (HDMEC) activities. Our studies indicate that the c-fiber-derived calcitonin gene-related peptide (CGRP) is capable of stimulating HDMEC to secrete the neutrophil chemotactic factor interleukin 8 (IL-8). In addition, SP is able to directly activate HDMEC to express high levels of the important cellular adhesion molecule vascular cellular adhesion molecule 1 (VCAM-1). Thus, these studies support the role that the neurologic system may play in mediating the biologic processes that occur during inflammation and wound healing in the skin.
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PMID:Interactions of the skin and nervous system. 948 11

Nitric oxide (NO) may regulate hepatic metabolism directly by causing alterations in hepatocellular (hepatocyte and Kupffer cell) metabolism and function or indirectly as a result of its vasodilator properties. Its release from the endothelium can be elicited by numerous autacoids such as histamine, vasoactive intestinal peptide, adenosine, ATP, 5-HT, substance P, bradykinin, and calcitonin gene-related peptide. In addition, NO may be released from the hepatic vascular endothelium, platelets, nerve endings, mast cells, and Kupffer cells as a response to various stimuli such as endotoxemia, ischemia-reperfusion injury, and circulatory shock. It is synthesized by nitric oxide synthase (NOS), which has three distinguishable isoforms: NOS-1 (ncNOS), a constitutive isoform originally isolated from neuronal sources; NOS-2 (iNOS), an inducible isoform that may generate large quantities of NO and may be induced in a variety of cell types throughout the body by the action of inflammatory stimuli such as tumor necrosis factor and interleukin (IL)-1 and -6; and NOS-3 (ecNOS), a constitutive isoform originally located in endothelial cells. Another basis for differentiation between the constitutive and inducible enzymes is the requirement for calcium binding to calmodulin in the former. NO is vulnerable to a plethora of biologic reactions, the most important being those involving higher nitrogen oxides (NO2-), nitrosothiol, and nitrosyl iron-cysteine complexes, the products of which (for example, peroxynitrite), are believed to be highly cytotoxic. The ability of NO to react with iron complexes renders the cytochrome P450 series of microsomal enzymes natural targets for inhibition by NO. It is believed that this mechanism provides negative feedback control of NO synthesis. In addition, NO may regulate prostaglandin synthesis because the cyclooxygenases are other hem-containing enzymes. It may also be possible that NO-induced release of IL-1 inhibits cytochrome P450 production, which ultimately renders the liver less resistant to trauma. It is believed that Kupffer cells are the main source of NO during endotoxemic shock and that selective inhibition of this stimulation may have future beneficial therapeutic implications. NO release in small quantities may be beneficial because it has been shown to decrease tumor cell growth and levels of prostaglandin E2 and F2 alpha (proinflammatory products) and to increase protein synthesis and DNA-repair enzymes in isolated hepatocytes. NO may possess both cytoprotective and cytotoxic properties depending on the amount and the isoform of NOS by which it is produced. The mechanisms by which these properties are regulated are important in the maintenance of whole body homeostasis and remain to be elucidated.
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PMID:The role of nitric oxide in hepatic metabolism. 959 11

We investigated whether an aqueous extract of Asparagus cochinchinensis Merrill (Liliaceae) roots (ACAE) inhibits secretion of tumor necrosis factor-alpha (TNF-alpha) from primary cultures of mouse astrocytes. ACAE dose-dependently inhibited the TNF-alpha secretion by astrocytes stimulated with substance P (SP) and lipopolysaccharide (LPS). IL-1 has been shown to elevate TNF-alpha secretion from LPS-stimulated astrocytes while having no effect on astrocytes in the absence of LPS. We therefore investigated whether IL-1 mediated inhibition of TNF-alpha secretion from astrocytes by ACAE. Treatment of ACAE to astrocytes stimulated with both LPS and SP decreased IL-1 secretion. Moreover, incubation of astrocytes with IL-1 antibody abolished the synergistic cooperative effect of LPS and SP. These results suggest that ACAE may inhibit TNF-alpha secretion by inhibiting IL-1 secretion and that ACAE has a antiinflammatory activity in the central nervous system.
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PMID:Inhibitory effect of Asparagus cochinchinensis on tumor necrosis factor-alpha secretion from astrocytes. 973 Feb 51

Explants of tissue derived from the medial collateral ligament (MCL) of normal and pregnant NZW rabbits cultured in the presence of substance P (SP), calcitonin gene-related peptide (CGRP), or both neuropeptides were found to have altered mRNA levels for a number of relevant molecules. Using a very efficient RNA isolation method, semi-quantitative RT-PCR and rabbit-specific primers, mRNA for growth factors (TGFbeta, bFGF, IGF-2, ET-1), cytokines (IL-1, TNF), enzymes (COX-2, iNOS), metalloproteinases (collagenase, stromelysin) and metalloproteinase inhibitors (TIMP-1, TIMP-2) were assessed after culture with or without neuropeptide. The results indicate that SP was effective in lowering mRNA levels for all of the molecules assessed in RNA from normal ligaments except IL-1beta, IGF-2 and TIMP-1, for which there was no significant effect. Similarly, CGRP was effective in lowering mRNA levels for all molecules except TNF, ET-1 and the TIMPs. The extent of the lowering of mRNA levels was both molecule-specific and neuropeptide-specific. When the experiments were repeated with ligament tissue from pregnant animals, a very different pattern of responsiveness to the neuropeptides was observed. While mRNA levels for 9/12 genes assessed were significantly affected by SP when normal MCL tissue was investigated, pregnancy abolished all significant responsiveness to this neuropeptide except for iNOS mRNA levels. In the case of iNOS mRNA, SP induced an increase in the steady-state levels, the opposite to what was observed with tissue from non-pregnant animals. For CGRP and SP+CGRP, tissue from pregnant animals was still responsive, but the pattern of responsiveness was changed from strictly a lowering of steady-state mRNA levels to elevations in mRNA levels for a number of genes. These findings indicate that mRNA levels for a number of genes can be influenced by neuropeptides known to be in ligaments. Thus, neuropeptides likely are important regulators of ligament cell metabolism. As the responsiveness to SP was nearly completely abolished during pregnancy, neuroregulatory influences mediated by this peptide are altered in the pregnant female. This loss of responsiveness to SP may also be one aspect of the analgesia associated with pregnancy.
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PMID:Pregnancy alters the in vitro responsiveness of the rabbit medial collateral ligament to neuropeptides: effect on mRNA levels for growth factors, cytokines, iNOS, COX-2, metalloproteinases and TIMPs. 978 99

Intrathecal (i.t.) injection (between lumbar vertebrae 5 and 6) into mice of a markedly low dose of IL-1alpha (3x10(-4) fmol or 5.4 fg in 5 microl per mouse) induced behaviors involving scratching, biting, and licking of non-stimulated hindpaws. The IL-1-induced behaviors appeared within 10 min of the injection of IL-1alpha, peaked at 20-40 min, and had disappeared 60 min after the injection. The IL-1-induced behaviors were similar to the nociceptive responses induced in mice by i.t. injection of substance P (SP) or subcutaneous (s.c.) injection of formalin into the footpad. The IL-1-induced behaviors were suppressed by intraperitoneal morphine, indicating that they are nociceptive responses. The nociceptive responses induced by 3x10(-4) (5.4 fg) of IL-1alpha were almost completely suppressed by co-injection of 0.3 fmol (7.2 pg) of an IL-1 receptor antagonist (IL-1ra). An antiserum against substance P, but not an antiserum against somatostatin, suppressed the IL-1-induced nociceptive responses. The nociceptive responses induced by s.c. injection of 2% formalin into the footpad were also inhibited by i.t. injection of 30 pmol (720 ng) of IL-1ra. These results suggest that IL-1 may play a role in hyperalgesia in mice by acting as a factor augmenting pain transmission in the spinal cord at least in part by either directly or indirectly releasing substance P.
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PMID:Induction of nociceptive responses by intrathecal injection of interleukin-1 in mice. 1044 10

The neurological system plays an important role in modulating some inflammatory skin diseases. Neuro-cutaneous interactions may be mediated by the release of neuropeptides such as substance P (SP) which activate immunocompetent cells in the skin by binding to high affinity neurokinin receptors (NKR). Since epidermal keratinocytes produce a variety of cytokines and are intimately associated with cutaneous sensory fibers, we tested the ability of these cells to participate in the cutaneous neuroimmune system by the secretion of potent cytokines such as interleukin 1 (IL-1) in response to released SP. RT-PCR studies demonstrated that cultured PAM 212 murine keratinocytes expressed mRNA for NK-2R but not NK-1R. Correspondingly, the addition of SP to these cells resulted in a rapid increase in intracellular Ca2+ levels that could be specifically blocked by an NK-2R antagonist. NK-2R was also shown in normal mouse epidermis by immunohistochemistry. SP augmented the expression of PAM 212 keratinocyte IL-1alpha mRNA in a dose and time dependent manner and this induction was inhibited by an NK-2R antagonist. Secretion of bioactive IL-1alpha by the PAM 212 keratinocytes was likewise stimulated by SP in a dose dependent manner. These data support the hypothesis that SP released from cutaneous sensory nerves contributes to neuroimmune inflammatory responses in the skin by modulating the expression and release of cytokines from epidermal keratinocytes.
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PMID:Substance P induction of murine keratinocyte PAM 212 interleukin 1 production is mediated by the neurokinin 2 receptor (NK-2R). 1068 74

There is accumulating evidence for a strong interaction between components of the nervous system and the immune system. Accordingly, specific receptors for neuropeptides were found to be expressed on immunocompetent cells and several neuropeptides were recognized as potent regulators of immune and inflammatory reactions. Among various neuropeptides such as substance P, calcitonin gene-related peptide and others alpha-melanocyte-stimulating hormone (alpha-MSH) was found to be produced in the skin. Moreover, melanocortin receptor 1 which is specific for alpha-MSH and ACTH is expressed in the skin on keratinocytes, dendritic cells, macrophages and endothelial cells. In monocytes, macrophages and dendritic cells alpha-MSH inhibits the production and activity of immunoregulatory and proinflammatory cytokines such as IL-2, IFNgamma and IL-1. It downregulates the expression of costimulatory molecules such as CD86 and CD40 and induces the production of suppressor factors such as the cytokine synthesis inhibitory factor IL-10. On endothelial cells alpha-MSH is capable of downregulating the LPS-induced expression of adhesion molecules such as vascular cellular adhesion molecules and E-selectin. Moreover, the LPS-induced activation of transcription factors such as NFkappaB is downregulated by alpha-MSH. In a mouse model intravenous or topical application of alpha-MSH was found to inhibit the induction as well as the effector phase of a contact hypersensitivity reaction and to induce hapten-specific tolerance. Moreover, there is evidence that the N-terminal tripeptide of alpha-MSH is sufficient for its in vitro and in vivo immunomodulatory effects. These findings indicate that the production of immunosuppressing neuropeptides such as alpha-MSH by epidermal cells may play an essential role during the pathogenesis of immune and inflammatory reactions in the skin.
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PMID:alpha-melanocyte-stimulating hormone as a mediator of tolerance induction. 1072 12

Among various neuropeptides such as substance P, calcitonin gene-related peptide and others, alpha-melanocyte-stimulating hormone (alpha-MSH) was found to be produced in the skin. Moreover, melanocortin receptor 1 (MC-1R), which is specific for alpha-MSH and ACTH, is expressed in the skin on keratinocytes, dendritic cells, macrophages and endothelial cells. In monocytes, macrophages and dendritic cells alpha-MSH inhibits the production and activity of immunoregulatory and proinflammatory cytokines such as IL-2, IFN-gamma, TNF-alpha and IL-1. It downregulates the expression of costimulatory molecules such as CD86 and CD40 and induces the production of suppressor factors such as the cytokine synthesis inhibitory factor IL-10. On endothelial cells alpha-MSH is capable of downregulating the LPS-induced expression of adhesion molecules such as vascular cell adhesion molecule (VCAM) and E-selectin. Moreover, the LPS-induced activation of transcription factors such as NF kappa B is downregulated by alpha-MSH. In a mouse model i.v. or topical application of alpha-MSH was found to inhibit the induction phase as well as the effector phase of contact hypersensitivity (CHS) reactions and to induce hapten-specific tolerance. These findings indicate that the production of immunosuppressing neuropeptides such as alpha-MSH by epidermal cells may play an essential role during the pathogenesis of immune and inflammatory reactions in the skin.
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PMID:The role of alpha-MSH as a modulator of cutaneous inflammation. 1126 49


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