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 examined the effects of ciliary neurotrophic factor (CNTF) and depolarization, two environmental signals that influence noradrenergic and cholinergic function, on neuropeptide expression by cultured sympathetic neurons. Sciatic nerve extract, a rich source of CNTF, increased levels of vasoactive intestinal peptide (VIP), substance P, and somatostatin severalfold while significantly reducing levels of neuropeptide Y (NPY). No change was observed in the levels of leu-enkephalin (L-Enk). These effects were abolished by immunoprecipitation of CNTF-like molecules from the extract with an antiserum raised against recombinant CNTF, and recombinant CNTF caused changes in neuropeptide levels similar to those of sciatic nerve extract. Alterations in neuropeptide levels by CNTF were dose-dependent, with maximal induction at concentrations of 5-25 ng/ml. Peptide levels were altered after only 3 days of CNTF exposure and continued to change for 14 days. Depolarization of sympathetic neuron cultures with elevated potassium elicited a different spectrum of effects; it increased VIP and NPY content but did not alter substance P, somatostatin, or L-Enk. Depolarization is known to block cholinergic induction in response to heart cell conditioned medium and we found that it blocked the induction of choline acetyltransferase (ChAT) and peptides by recombinant cholinergic differentiation factor/leukemia inhibitory factor (CDF/LIF). In contrast, it did not antagonize the effects of CNTF on either ChAT activity or neuropeptide expression. Thus, while CNTF has effects on neurotransmitter properties similar to those previously reported for CDF/LIF, the actions of these two factors are differentially modulated by depolarization, suggesting that the mechanisms of cholinergic and neuropeptide induction for the two factors differ. In addition, in contrast to CDF/LIF, CNTF did not alter levels of ChAT, VIP, substance P, or somatostatin in cultured dorsal root ganglion neurons. These observations indicate that CNTF and depolarization affect the expression of neuropeptides by sympathetic neurons and provide evidence for an overlapping yet distinct spectrum of actions of the two neuronal differentiation factors, CNTF and CDF/LIF.
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PMID:Effects of ciliary neurotrophic factor (CNTF) and depolarization on neuropeptide expression in cultured sympathetic neurons. 137 70

The nervous and immune systems interact in a bidirectional fashion. For example, the neuropeptide substance P (SP) has been implicated in a variety of immune responses. Conversely, cytokines, a class of immunoregulatory glycoproteins, affect the synthesis of neurotransmitters and neurotrophic factors. This paper examines the role of cytokines in regulating neuropeptide expression in sympathetic neurons. Exposure of cultured explants of the rat superior cervical ganglion to the cytokine interleukin 1 beta (IL-1 beta) increased levels of SP. IL-1 beta increased neuronal SP expression in dissociated cultures of ganglion neuronal and nonneuronal cells but had no effect on peptide content in pure neuronal cultures. By contrast, treatment with a differentiation-promoting protein, leukemia inhibitory factor, increased SP in both pure neuronal and mixed cultures, indicating a different mechanism of action for the two molecules. The specificity of the IL-1 beta effect was further demonstrated by the lack of response to treatment with other cytokines, including interleukin 2, interleukin 6, and tumor necrosis factor alpha. The cell type necessary for the IL-1 beta activity is probably the ganglion Schwann cell. Treatment with a synthetic immunosuppressant glucocorticoid, dexamethasone, blocked the increase in SP after treatment with IL-1 beta. These observations support the hypothesis that neuropeptide expression is regulated, in part, by interactions with specific immunoregulators. In addition, the data suggest a role for SP in mediating the response of the superior cervical ganglion to injury of the ganglion itself or to the fibers innervating it.
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PMID:Cytokine regulation of substance P expression in sympathetic neurons. 170 35

The cholinergic differentiation factor (CDF) in heart cells is identical to leukemia inhibitory factor (LIF). Recombinant CDF/LIF was shown to alter dramatically neurotransmitter production as well as the levels of several neuropeptides in cultured rat sympathetic neurons. Here it is shown that these changes are likely to be caused by alterations in the mRNA for these proteins and peptides. Growth in 1 nM recombinant CDF/LIF induces mRNA for acetyl CoA: choline-O-acetyltransferase [EC 2.3.1.6; choline acetyltransferase (ChAT)], somatostatin (SOM), substance P, and vasoactive intestinal polypeptide while lowering mRNA levels of tyrosine hydroxylase (EC 1.14.16.2) and neuropeptide Y (NPY). In addition, the sizes of the mRNAs for ChAT, SOM, and NPY are larger after recombinant CDF/LIF treatment.
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PMID:Recombinant cholinergic differentiation factor (leukemia inhibitory factor) regulates sympathetic neuron phenotype by alterations in the size and amounts of neuropeptide mRNAs. 190 72

Effects of immune cytokines on neuronal gene expression have recently been examined in cultured superior cervical (sympathetic) ganglia, a widely used model system for the study of neurotransmitter plasticity. Following deafferentation and explantation into culture, interleukin-1 causes an up-regulation of the neuropeptide substance P as well as of choline acetyltransferase. Tumor necrosis factor-alpha has a similar, though less potent, action. Since interleukin-1 was ineffective in raising the concentration of substance P in pure neuronal cultures, the existence of a non-neuronally derived intermediate was postulated and found to exist in interleukin-1-conditioned medium. Antibody neutralization of either nerve growth factor or ciliary neurotrophic factor failed to affect the ability of interleukin-1 to induce substance P. Inhibition of prostaglandin biosynthesis was equally ineffective. However, immunoprecipitation of leukemia inhibitory factor from interleukin-1-conditioned medium eliminated substance-P-inducing activity, suggesting leukemia inhibitory factor as a possible interleukin-1-induced intermediate. The ability of interleukin-1 to induce leukemia inhibitory factor mRNA strengthens this conclusion. Glucocorticoid hormones block the interleukin-1 induction of leukemia inhibitory factor, which explains why they block the interleukin-1 induction of substance P.
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PMID:Neural-immune interactions in sympathetic ganglia. 752 15

The neurotransmitter phenotype switch that occurs in cultures of rat superior cervical ganglion neurons after treatment with leukemia inhibitory factor or ciliary neurotrophic factor is a useful model permitting investigation of the mechanisms of cytokine-mediated differentiation. Recently the actions of leukemia inhibitory factor and ciliary neurotrophic factor have been linked through their interactions with related receptor complexes. Here we compare the effects of these two cytokines on gene expression in sympathetic neuronal cultures and begin to investigate their mechanisms. We report that, as has been shown for leukemia inhibitory factor, ciliary neurotrophic factor regulates peptides and classical transmitters in these cultures at the mRNA level. In addition, we find that the induction of substance P mRNA by these cytokines is rapid, dependent on protein synthesis, and occurs in 40-50% of superior cervical ganglion neurons in dissociated culture.
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PMID:Coordinate regulation of choline acetyltransferase, tyrosine hydroxylase, and neuropeptide mRNAs by ciliary neurotrophic factor and leukemia inhibitory factor in cultured sympathetic neurons. 751 94

Interleukin-1 (IL-1) induction of substance P (SP) in cultured sympathetic ganglia requires a soluble intermediate molecule that is present in IL-1 conditioned medium (IL-1CM). One of the required intermediates is leukemia inhibitory factor (LIF; Shadiack et al., J Neurosci 13:2601-2609, 1993). In the present study we have examined the possibility that ciliary neurotrophic factor (CNTF) is another intermediate involved in the IL-1 induction of sympathetic SP. CNTF mimics the action of IL-1CM by raising both SP and choline acetyltransferase activity--actions that are blocked by a specific neutralizing antiserum for CNTF. However, IL-1CM and CNTF differ in their response to depolarizing agents: while KCl (40 mM) blocks the action of IL-1CM (and LIF), it enhances the action of CNTF. Furthermore, neither CNTF bioactivity nor CNTF protein is detected in IL-1CM. Neutralizing antiserum to CNTF fails to block the action of either IL-1 or IL-1CM, suggesting that neither a soluble nor a membrane-bound form of the molecule is active in direct response to IL-1 action. While Northern blots confirm the presence of both CNTF and CNTF receptor mRNA in neonatal ganglia, neither culturing nor IL-1 treatment alters these mRNA levels. These data taken together suggest that while CNTF is present and possibly active in sympathetic ganglia, it is not a mediator of the IL-1 induction of SP.
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PMID:The interleukin-1-induced increase of substance P in sympathetic ganglia is not mediated by ciliary neurotrophic factor. 752 14

Previously, we showed that c-kit receptor tyrosine kinase is expressed by a subpopulation of dorsal root ganglion (DRG) neurons, and that the ligand for the c-kit receptor, stem cell factor (SCF), induces the neurite outgrowth and supports the survival of these neurons in culture [16]. However, it is unknown which class of DRG neurons express c-kit receptor and which factor regulates differentiation and survival of c-kit-positive neurons. In the present study, we attempted to characterize c-kit positive neurons in the mouse DRG. The c-kit-positive neurons were small or medium in size, and 44% of these neurons contained substance P. Central fibers of the c-kit-positive neurons terminated in laminae I and II of the gray matter of the spinal cord. These results suggest that c-kit-positive neurons in the DRG belong to a functional subpopulation. The c-kit receptor protein was presented on the membrane of processes and growth cones in neurons. When DRG cells of embryonic day 15.5 or 17.5 were cultured, the survival of c-kit-positive neurons was supported by SCF, nerve growth factor (NGF) or leukemia inhibitory factor. SCF and NGF synergistically supported the survival of c-kit-positive neurons at submaximal concentrations. c-kit-positive DRG neurons from neonatal mice survived without addition of any factor in culture, suggesting that the requirement for trophic support in c-kit-positive neurons changes during development.
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PMID:Characterization of c-kit-positive neurons in the dorsal root ganglion of mouse. 754 20

Regulation of substance P receptor (SPR) mRNA was examined in the rat sympathetic superior cervical ganglion (SCG) in vitro and in vivo after axotomy. Interleukin-1 beta (IL-1 beta) treatment of explanted ganglia elevated levels of SPR mRNA. By contrast, dissociated cultures of purified sympathetic neurons, purified fibroblasts, and purified Schwann cells each expressed only low levels of SPR mRNA, and treatment with the cytokine did not alter levels of the receptor mRNA. Treatment of Schwann cell or fibroblast cultures with leukemia inhibitory factor (LIF) also did not alter SPR mRNA. However, treatment of pure neuronal cultures with LIF significantly elevated levels of the receptor mRNA. Further, SPR mRNA increased in pure sympathetic neurons cultured in the presence of conditioned medium from IL-1 beta treated fibroblasts or Schwann cells; this effect was blocked in the presence of LIF antibody. This suggests that the stimulatory effects of IL-1 beta on SPR mRNA in explants is mediated by LIF release. Axotomy of the SCG in vivo resulted in a significant increase in LIF mRNA. Further, axotomy resulted in a significant increase in SPR mRNA, suggesting that LIF may mediate the increase in SPR mRNA. In view of the known effects of substance P (SP) on inflammatory responses, these observations suggest that coordinated expression of SP and SPR mRNA in neurons after nerve injury may participate in inflammatory and repair processes in the ganglion.
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PMID:LIF-and IL-1 beta-mediated increases in substance P receptor mRNA in axotomized, explanted or dissociated sympathetic ganglia. 758 37

Three myelopoietically active, lipopolysaccharide (LPS)-stimulated monokines, interleukin-1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF-alpha), and leukemia inhibitory factor (LIF), were tested for effect in an in vitro model for LPS-induced inflammatory murine monocytopoiesis. Neither cytokine stimulated clonal proliferation of marrow-derived progenitors; however, both IL-1 alpha and TNF-alpha enhanced macrophage colony-stimulating factor (M-CSF)-dependent colony formation. The additional progenitors stimulated by IL-1 alpha and TNF-alpha to form colonies in response to M-CSF were equivalent to the precommitment, transitional progenitors stimulated by M-CSF and bacterial LPS. In addition, the additional colonies elicited by IL-1 alpha and TNF-alpha were not additive in cultures containing both M-CSF and LPS, indicating these colonies arose from the same LPS-responsive, two-signal-dependent transitional progenitors. Leukemia inhibitory factor did not influence M-CSF-stimulated colony formation; however, LIF effected a dose-dependent inhibition of colony formation by transitional progenitors responding to combinations of M-CSF and LPS, IL-1 alpha, TNF-alpha, or an additional transitional cell costimulant, substance P. Neutralizing anti-murine TNF-alpha antibodies abrogated transitional cell colony formation stimulated by combinations of M-CSF and TNF-alpha, IL-1 alpha, LPS, or substance P but had no effect on colony formation stimulated solely by M-CSF. The results indicate that TNF-alpha may be an important positive stimulus for commitment of progenitors to the mononuclear phagocyte lineage and that TNF-alpha may be the endogenous regulator of the costimulatory effects of LPS, IL-1, and substance P. In addition, the results indicate that LIF may play an opposing negative regulatory role acting to inhibit LPS and TNF-alpha stimulation of the transitional progenitors.
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PMID:Opposing effects of tumor necrosis factor alpha and leukemia inhibitory factor in lipopolysaccharide-stimulated myelopoiesis. 767 84

It has become increasingly clear that immune cytokines perform growth and differentiation functions in the nervous system similar to those performed in the immune system. In previous studies we have shown that interleukin-1 beta (IL-1 beta) raises substance P (SP) and the mRNA coding for its preprotachykinin precursor in cultured sympathetic superior cervical ganglia (SCG) (Jonakait and Schotland, 1990; Hart et al., 1991a). The action of IL-1 is blocked both by depolarization of the ganglia and by glucocorticoid hormones (Hart et al., 1991a). In the present report, we have found that IL-1 does not act directly upon neurons to raise SP, but rather induces the production of a soluble intermediate molecule that raises both SP and the cholinergic-specific enzyme ChAT. Its induction by IL-1 is blocked by the synthetic glucocorticoid hormone dexamethasone; its action is compromised under depolarizing conditions. Because medium conditioned by IL-1 (IL-1CM) is functionally similar to leukemia inhibitory factor (LIF), we sought to determine whether this molecule might be an active constituent of IL-1CM. Immunoprecipitation with an antiserum directed against LIF eliminated large proportions of SP-inducing activity from IL-1CM. In addition, steady-state levels of mRNA coding for LIF are increased by IL-1 treatment of SCG. These data suggest that LIF, induced by IL-1, may ultimately be responsible for the IL-1 induction of SP.
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PMID:Interleukin-1 induces substance P in sympathetic ganglia through the induction of leukemia inhibitory factor (LIF). 768 75


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