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 interactions between IL-1 and several neuropeptides associated with pain and inflammation were examined in the context of fibroblast proliferation as a paradigm for the synovial hyperplasia associated with chronic rheumatoid arthritis. The BALB/3T3 fibroblast cell line, which proliferates in response to increasing doses of IL-1, demonstrated enhanced proliferation after a 72-h culture period when various neuropeptides were included with IL-1 in serum-free medium. Thus, bradykinin, at concentrations between 10(-8) and 10(-5) M, moderately promoted [3H]TdR incorporation in vitro in the BALB/3T3 cells, and substance P at approximately 3 x 10(-9) to 3 x 10(-7) M demonstrated minor proliferative activity. However, when the cells were cultured with IL-1 plus substance P or IL-1 plus BK, the ensuing proliferative responses, as measured by [3H]TdR incorporation, were consistently magnified greater than or equal to twofold above the anticipated additive response caused by IL-1 in combination with either of those neuropeptides. Combinations of IL-1 and SP, or IL-1 and BK, also provoked increases in cell numbers that did not occur when the mediators were tested individually. In other experiments, we tested neurokinin-A, Neurokinin-B, histamine, and serotonin. These results are discussed with respect to neurogenic contributions to the immunopathology of IL-1-mediated inflammation.
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PMID:Potentiation of IL-1-induced BALB/3T3 fibroblast proliferation by neuropeptides. 246 86

Kinins are vasoactive peptides whose potent inflammatory and bone resorbing properties suggest a role for these autacoids in the pathogenesis of inflammatory arthritis. We used cultured human synovial cells as a model to evaluate the effects of bradykinin on articular tissue. In resting synovial cells, bradykinin was a relatively ineffective stimulus for PGE2 production. However, after a period of preincubation with the cytokine, IL-1, which is itself a stimulus for PGE2 production, synovial cells exhibited a further striking time- and dose-dependent response to bradykinin. Maximal release of PGE2 was observed in response to 10(-7) to 10(-6) M bradykinin after first pretreating the cells for 24 h with 5 to 10 U/ml of IL-1. rIL-1 alpha and IL-1 beta, as well as rTNF-alpha, induced a similar response to bradykinin in synovial cells, whereas recombinant IL-2 did not. The bradykinin analog, lysylbradykinin, was equipotent in inducing PGE2 release from IL-1 pretreated synovial cells, whereas des(Arg9) bradykinin, substance P, and neurokinins A and B were ineffective in this regard in both IL-1-pretreated and in resting cells. Synovial cells derived from patients with rheumatoid arthritis and osteoarthritis responded similarly to bradykinin. The synergistic response in PGE2 production induced by IL-1 and bradykinin was significantly inhibited by pretreatment with 1 microM indomethacin or dexamethasone (96 and 94% inhibition, respectively). In addition, the response was abrogated by pretreatment with 10 micrograms/ml of cycloheximide or actinomycin D (81 and 97% inhibition, respectively). These data provide the first description of synergism of IL-1 with a noncytokine peptide in human synovial cells. The ability of IL-1 to increase the responsiveness of synovial tissues to bradykinin may play an important role in potentiating inflammatory responses within the joint.
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PMID:Preincubation of human synovial cells with IL-1 modulates prostaglandin E2 release in response to bradykinin. 247 45

The substance P (SP) fragment SP(7-11) induced chemiluminescence (CL) and aggregation in human neutrophils at high concentrations (greater than or equal to 10 microM), whereas the entire molecule SP(1-11) was less potent and the SP(1-4) fragment was inactive. At these concentrations SP and its fragments also inhibited CL and aggregation evoked by subsequent addition of formyl-methionyl-leucyl-phenylalanine (fMLP), an effect that may depend on desensitization. However, at lower concentrations (1-10 nM) SP was able to prime human neutrophils to enhanced CL and enzyme release stimulated by fMLP. These findings indicate that, in addition to direct activation of CL and aggregation, SP also modulates neutrophil function and can thus amplify the release of potentially cytotoxic substances, a possible mechanism for nervous system involvement in rheumatoid arthritis.
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PMID:Substance P activates and modulates neutrophil oxidative metabolism and aggregation. 247 43

The pronounced synovial hyperplasia often found in the joints of patients with rheumatoid arthritis could be explained partially by the action of monocyte-macrophage polypeptides (monokines). This report demonstrates that two cytokines which may be derived from monocyte-macrophage populations, namely platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), stimulate the DNA synthesis and proliferation of human synovial fibroblast-like cells cultured in low (i.e., 1%) fetal bovine serum. Epidermal growth factor, insulin-like growth factor-I, insulin-like growth factor-II (multiplication stimulating activity) and substance P were inactive. Unlike IL-1, PDGF and FGF do not also stimulate PGE2, plasminogen activator, and hyaluronic acid levels. Thus PDGF and FGF, arising from stimulated monocyte-macrophages, may play a role in the stimulation of mesenchymal cell proliferation that often accompanies chronic inflammatory arthritic disease. The synovial cells respond to a variety of cytokines in different ways suggesting multiple-signaling pathways.
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PMID:Stimulation of human synovial fibroblast DNA synthesis by platelet-derived growth factor and fibroblast growth factor. Differences to the activation by IL-1. 270 21

The regulatory peptide substance P has been implicated in the development and persistence of inflammatory synovitis. The authors used quantitative in vitro receptor autoradiography to compare synovial binding of 125Iodine-Bolton Hunter-labeled substance P ([125I]BH-SP) in rats and humans and between uniflamed and persistently inflamed synovium. [125I]BH-SP binding to microvascular endothelium paralleled the distribution of substance P-immunoreactive nerves and had characteristics of the neurokinin (NK) 1 class of tachykinin receptor. Specific binding was inhibited by the selective NK1 receptor antagonist, FK888, and the dual NK1/NK2 receptor antagonist FK224, with Hill coefficients near unity. FK888 was > 1000 times and FK224 > 10 times more potent at inhibiting binding in human compared with rat synovium. Synovium from patients and rats with chronic arthritis contained heterogeneously distributed inflammatory cell infiltrates. For the 10 microvessels with the densest [125I]BH-SP binding in each section, no significant differences in binding density, affinity, or Ki values for substance P, FK888 or FK224 were found between synovium from naive and monoarthritic rats, nor between that from patients with rheumatoid arthritis or osteoarthritis. However, in both rat and human specimens, microscopic examination suggested that microvascular [125I]BH-SP binding in intensely infiltrated regions of synovium was less dense than in adjacent, less infiltrated areas. It was concluded that NK1 receptors are similarly distributed in rat and human synovium but show major differences in selectivity for antagonists such as FK888. NK1 receptors in synovium may mediate proinflammatory actions of locally released substance P; defective neurovascular regulation may contribute to the persistence of chronic arthritis.
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PMID:Microvascular substance P binding to normal and inflamed rat and human synovium. 750 2

Bilateral changes in the spinal cord and dorsal root ganglion content of the sensory peptides substance P and calcitonin gene-related peptide have been previously reported in animal models of arthritis which affect many joints within the body. The central nervous system has been implicated in the symmetry of joint involvement in human rheumatoid arthritis. We aimed to determine whether unilateral inflammation of the knee joint can also induce bilateral changes in the spinal cord. We have induced a monoarthritis in the knee joint of the rat and used quantitative immunocytochemistry to look at changes of these peptides in the dorsal horn of the spinal cord and the dorsal root ganglia. Furthermore we have examined the responses during the acute (three days) and the chronic (21 days) phases of the model. The data show that in the acute phase of the monoarthritis there is both an ipsilateral and contralateral response which increases the immunoreactive substance P and calcitonin gene-related peptide in the L4 level of the dorsal horn of the spinal cord. In the chronic phase of the monoarthritis, the contralateral side of the dorsal horn returned to control values whilst the ipsilateral side showed reduced amounts of immunoreactive substance P and calcitonin gene-related peptide compared to controls. We propose that the acute response, at three days, to unilateral inflammation is appropriate and has evolved to protect an organism against the original insult ipsilaterally, and the possibility of subsequent insult contralaterally.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoarthritis in the rat knee induces bilateral and time-dependent changes in substance P and calcitonin gene-related peptide immunoreactivity in the spinal cord. 750 83

The feasibility of extracting neuropeptides from rat knee joints for quantitation by radioimmunoassay was tested. The investigation, based on 25 adult Lewis rats, focused on substance P, calcitonin gene-related peptide, neuropeptide Y, and vasoactive intestinal polypeptide. The relative recovery of the peptides in different extraction media was assessed Both knee joints including the articulating epiphysis were dissected and cut into small pieces. The series was divided into five subgroups, 10 joints in each, for extraction in five different media: 1) 1 M acetic acid in 4% EDTA, 2) 2 M acetic acid in 4% EDTA, 3) neutral water in 4% EDTA, 4) 2 M acetic acid in 4% EDTA and 95% alcohol, and 5) 2 M acetic acid without EDTA. Measureable concentrations of the four neuropeptides were reproducibly assessed by RIA. Although all extraction media provided measurable concentrations, 2 M acetic acid in 4% EDTA was found to give the highest overall yield of the four neuropeptides analyzed. Reverse-phase HPLC confirmed that the immunoreactivities assessed by RIA corresponded to the four neuropeptides of interest. Experimental and clinical evidence suggest a neurogenic involvement in the pathophysiology of inflammatory joint disease, e.g., rheumatoid arthritis. The extraction procedure described offers a means of determining neuropeptide concentrations in joint tissue under normal and pathologic conditions by RIA.
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PMID:Extraction of neuropeptides from joint tissue for quantitation by radioimmunoassay. A study in the rat. 751 57

Plasma and synovial fluid concentrations of interleukin-6 (IL-6), using an enzyme-linked immunosorbent assay, as well as immunoreactive levels of calcitonin gene-related peptide (CGRP), substance P and vasoactive intestinal peptide (VIP) were measured in 18 patients with rheumatoid arthritis and 20 with osteoarthritis of the knee. The concentrations of IL-6 were elevated in both plasma and synovial fluids from patients with rheumatoid arthritis whereas higher levels of substance P-, CGRP- and VIP-like immunoreactivities were found in the synovial fluid, but not in plasma, from patients with rheumatoid arthritis when compared with those in osteoarthritis. Furthermore, IL-6 and substance P levels in synovial fluid were significantly correlated both in rheumatoid arthritis and osteoarthritis patients. Our data seem to support the idea of an important role shared by neuropeptides and IL-6 in the pathogenesis of human inflammatory joint disease.
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PMID:Neuropeptides and interleukin-6 in human joint inflammation relationship between intraarticular substance P and interleukin-6 concentrations. 752 Jan 39

Substance pertains to a group of linear molecules of 10-30 amino-acid residues produced by nervous fibers and called neuropeptides. It is a mediator of pain transmission, and modulates or stimulates the activity of several cell types, i.e. lymphocytes and mast cells. The concept of neurogenic inflammation is based on the release of substance P and related peptides by an axon eflex mechanism. In rheumatic diseases, substance P may enhance inflammatory joint reactions. In rheumatoid arthritis, high SP levels were demonstrated in synovial fluid by our group and others. Results in fibromyalgia are contradictory. Algoneurodystrophia may be modulated by substance P release. Topical use or capsaicin and development of peripheral inhibitory drugs offer novel treatments based on this concept.
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PMID:[Substance P and rheumatic diseases]. 752 32

Various factors determine the outcome of rheumatoid arthritis and juvenile chronic arthritis. One of these factors is the neuro-endocrine system. In rheumatoid arthritis as well as in juvenile chronic arthritis, alterations of the autonomous nervous system do occur. In polyarticular and systemic juvenile chronic arthritis, during active disease the sensitivity for catecholamines changes. Under these conditions catecholamines cannot inhibit the immune response, which may have negative consequences for the course of the disease. In certain autoimmune animal models defects in the hypothalamus-pituitary-adrenal axis play a role in the pathogenesis of the disease. Studies in rheumatoid arthritis suggest a subtle insufficiency of the hypothalamus-pituitary-adrenal-axis in rheumatoid arthritis. Proinflammatory substances such as Substance P, as well as (locally produced) opioids may contribute to disease activity.
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PMID:Rheumatoid arthritis and juvenile chronic arthritis: the role of the neuro-endocrine system. 752 32


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