Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3H-Labelled kappa-elastin peptides (kE:75 kDa molecular weight) were shown to bind to confluent human skin fibroblast (HSF) cultures in a time-dependent and saturable manner. Scatchard analysis indicated the presence of high affinity binding sites with kD = 2.7 x 10(-10) M and 19,000 sites per cell. Binding of kE to its receptor on HSF accelerates and intensifies the adhesion of insoluble elastin fibres (iE) to confluent HSF. Optimal effect was attained for a kE concentration of 0.3 x 10(-9) M close to kD. This stimulatory effect of kE on the binding of iE to HSF could be inhibited by neomycin, retinal and pertussis toxin, substances which act at different levels of the transduction mechanism following the activation of the receptor and the subsequent triggering of cell biological events (chemotaxis, modification of calcium fluxes). The stimulation of iE adhesion to HSF induced by kE as well as kE binding to the cells could be inhibited by lactose and laminin but not by Arg-Gly-Asp-Ser(RGDS) peptides. This indicates that the elastin peptide receptor on HSF possesses lectin-like properties and shares homology with the laminin receptor as also shown for other cell types. None of the substances tested, that is inhibitors of the transduction mechanism, lactose, laminin and Arg-Gly-Asp-Ser(RGDS) peptides were shown to interfere significantly with the binding of iE (in the absence of added kE) to confluent HSF. The proteins adhering strongly to elastin fibres were isolated by a sequential extraction procedure and the final hydrochloride guanidinium-DTT extract was analysed by SDS-PAGE under reducing conditions, Western blots using specific antibodies against several connective tissue proteins and affinity for [3H]-kE following nitrocellulose electro-transfer of proteins. Fibronectin, vitronectin, tropoelastin(s), and a 120 kDa cysteine rich glycoprotein previously designated as elastonectin were identified. Among these proteins, [3H]-kE was found to bind exclusively to a 65 kDa protein that could be eluted selectively from elastin fibres with a neutral buffer containing 100 mM lactose. Therefore the elastin peptide receptor on human skin fibroblasts shares properties with the elastin receptor characterized from other cell types. Conformational differences between elastin peptides and elastin fibres could explain the differences in the mechanisms of interactions between elastin fibres and elastin peptides with HSF in culture. The stimulatory effect of elastin-derived peptides on the adhesion of elastin fibres to HSF could have implications in the oriented biosynthesis of elastin fibres.
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PMID:Mechanisms of interaction between human skin fibroblasts and elastin: differences between elastin fibres and derived peptides. 172 59

The degradation of elastic fibres during atherosclerotic plaque formation in arterial wall is a well known process. The liberated elastin peptides such as K-elastin possess various biological activities: They are chemotactic for monocytes and fibroblasts, stimulate the oxidative burst and the intracellular free Ca2+ mobilisation through the phosphatidylinositol (PIP2) breakdown in PMNLs. It was found that the PIP2 breakdown induced by K-elastin is a pertussis toxin sensitive process in PMNLs of young subjects. In the case of the elderly, the K-elastin-induced oxidative burst, intracellular free Ca2+ elevation was less than in young, and could not be inhibited by pertussis toxin. Studying the K-elastin-induced inositol phosphate (IP) formation in PMNLs of elderly a disturbed PIP2 breakdown was found. K-elastin stimulated the IP formation at a very low level in PMNLs of elderly. This alteration of the second messenger formation (e.g. IP3 and Ca2+) after KE stimulation, might be the consequence of their originally elevated levels in resting PMNLs of elderly.
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PMID:Altered phosphatidylinositol breakdown after K-elastin stimulation in PMNLs of elderly. 215 16

Studies were undertaken to evaluate factors capable of influencing the intensity of contact hypersensitivity (CH) and delayed-type hypersensitivity (DTH) responses in mice. It is well known that the exposure of animals to ultraviolet radiation (UVR) causes a depression of CH and DTH responses whereas the injection of mice with nanogram quantities of pertussis toxin (PT) before sensitization results in greatly augmented CH responses following hapten challenge. Histopathology and biochemical quantitation of myeloperoxidase (MPO) activity in biopsies obtained from the challenged ears from normal, UVR-exposed, or PT-treated animals determined that a direct correlation existed between the intensity of the ear-swelling response and the degree of neutrophil infiltrate into the challenge site. Few neutrophils were observed to infiltrate into the ears of UVR-exposed animals when compared to normal animals, whereas a pronounced neutrophil infiltration was observed in the challenged ears of PT-pretreated animals. These observations led us to question whether tissue-infiltrating neutrophils, or their products, might be involved in controlling the intensity of CH and DTH responses. The direct injection of murine neutrophils, neutrophil homogenates, and a neutrophil granular fraction into the ear pinnae of normal mice resulted in a dosage-dependent ear-swelling reaction after 24 hours that was histologically similar to antigen-induced CH or DTH responses (primarily mononuclear cell infiltrate). Additional studies determined that an injection of elastase, collagenase, or peptides of elastin or collagen generated by elastase or collagenase treatment of insoluble elastin or collagen also caused a pronounced ear-swelling accompanied by a mononuclear cell infiltration. On the basis of these studies, coupled to experiments that demonstrated an inhibitory influence of alpha-1-antitrypsin (alpha 1-AT) on CH and DTH responses, we propose that neutrophil proteases may play an important role in regulating the intensity of CH and DTH responses in mice through their capacity to degrade extracellular matrix proteins whose peptide fragments are chemotactic for mononuclear cells and fibroblasts.
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PMID:The role of neutrophils in tissue localized cell-mediated immunologic responses: I. The intensity of contact-type and delayed-type hypersensitivity responses may be influenced by the extent of extracellular matrix degradation by neutrophil proteases. 285 42

The effect of elastin peptides (kappa-elastin, KE) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) on cytosolic free calcium in polymorphonuclear leukocytes (PMNLs) of healthy middle-aged (35-45 years) and elderly (greater than 60 years) patients with normal and high serum cholesterol level was investigated. The cytosolic free calcium [( Ca2+]i) elevation after stimulation with these compounds was decreased in PMNLs of the aged groups compared to the healthy middle-aged group. The guanine nucleotide binding regulatory Gi protein inhibitor, pertussis toxin (PT) prevented the enhancing effect of KE and FMLP on PMNL free calcium of healthy middle-aged subjects, but could not completely abolish the [Ca2+]i elevation in PMNLs of aged subjects.
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PMID:Effect of elastin peptides and N-formyl-methionyl-leucyl phenylalanine on cytosolic free calcium in polymorphonuclear leukocytes of healthy middle-aged and elderly subjects. 339 Aug 98

It is well demonstrated that various peptides derived from elastin are biologically active. The hexapeptide (Val-Gly-Val-Ala-Pro-Gly; VI) as well as elastin peptides were demonstrated to be chemotactic for fibroblasts, while kappa-elastin had marked biological effects on human PMNLs. The aim of our present work was to synthesize various elastin peptides and compare their action to that of kappa-elastin and this hexapeptide. The results indicate that the hexapeptide (Val-Gly-Val-Ala-Pro-Gly) and the two other synthesized hexapeptides (Pro-Gly-Val-Gly-Val-Ala; III and Val-Gly-Val-Gly-Val-Ala; IV) had very similar and specific effects on intracellular free calcium metabolism, on superoxide anion production and elastase release. The other peptides had no effects on these parameters, except a tripeptide (Val-Gly-Val; V) on superoxide anion production. Moreover, the effect of the hexapeptides (III and VI) could be abolished by Pertussis toxin preincubation. All peptides had very similar stimulating effects on H2O2 production and myeloperoxidase release. We conclude that most probably the peptide size and conformation, as well as peptide composition play a role in the biological effects of these peptides, through specific receptors on PMNLs surface.
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PMID:Effects of synthesized elastin peptides on human leukocytes. 865 87

We have established that treatment of cultured human skin fibroblasts with tropoelastin or with heterogenic peptides, obtained after organo-alkaline or leukocyte elastase hydrolysis of insoluble elastin, induces a high expression of pro-collagenase-1 (pro-matrix metalloproteinase-1 (pro-MMP-1)). The identical effect was achieved after stimulation with a VGVAPG synthetic peptide, reflecting the elastin-derived domain known to bind to the 67-kDa elastin-binding protein. This clearly indicated involvement of this receptor in the described phenomenon. This notion was further reinforced by the fact that elastin peptides-dependent MMP-1 up-regulation has not been demonstrated in cultures preincubated with 1 mm lactose, which causes shedding of the elastin-binding protein and with pertussis toxin, which blocks the elastin-binding protein-dependent signaling pathway involving G protein, phospholipase C, and protein kinase C. Moreover, we demonstrated that diverse peptides maintaining GXXPG sequences can also induce similar cellular effects as a "principal" VGVAPG ligand of the elastin receptor. Results of our biophysical studies suggest that this peculiar consensus sequence stabilizes a type VIII beta-turn in several similar, but not identical, peptides that maintain a sufficient conformation to be recognized by the elastin receptor. We have also established that GXXPG elastin-derived peptides, in addition to pro-MMP-1, cause up-regulation of pro-matrix metalloproteinase-3 (pro-stromelysin 1). Furthermore, we found that the presence of plasmin in the culture medium activated these MMP proenzymes, leading to a consequent degradation of collagen substrate. Our results may be, therefore, relevant to pathobiology of inflammation, in which elastin-derived peptides bearing the GXXPG conformation (created after leukocyte-dependent proteolysis) bind to the elastin receptor of local fibroblasts and trigger signals leading to expression and activation of MMP-1 and MMP-3, which in turn exacerbate local connective tissue damage.
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PMID:Conformational dependence of collagenase (matrix metalloproteinase-1) up-regulation by elastin peptides in cultured fibroblasts. 1108 20

With aging we assist to alterations in the vascular structure and function. One important factor in these vascular wall changes is the degradation of the elastin fibre major protein: elastin. Elastin peptides derived from the degradation are present in human sera. Elastin peptides induce on fibroblasts, phagocytic cells, lymphocytes, smooth muscle cells and endothelial cells, a variety of biological effects mediated by the elastin-laminin receptor which has been demonstrated to be present on the membrane of these cells. The transduction pathway of the ELR receptor involves the activation of phospholipase C (PLC) by a pertussis toxin sensitive G-protein. PLC induces the production of inositol trisphosphate (IP3) leading to the increase of the intracellular free calcium on one hand, and of diacylglycerol (DAG) which stimulates the translocation to the membrane of PKC leading to the phosphorylation of members of the MAPK family, such as p42/p44 MAPK. A progressive age dependent uncoupling of the elastin-laminin receptor occurs impairing its transduction pathway and which results in alteration of the calcium signaling and loss in calcium homeostasis of the cells. These alterations in the signal transduction of the elastin-laminin receptor result in modified activities of parenchymal and phagocytic cells with aging, such as free radical production and elastase release. Thus, these age-related alterations in the elastin-laminin receptor signal transduction may be involved in the atherogenesis.
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PMID:Age-related alterations in the signal transduction pathways of the elastin-laminin receptor. 1142 70

Elastin is a major component of the extracellular matrix. Elastin peptides derived from its degradation are present in human sera. Elastin peptides induce on fibroblasts, phagocytic cells, lymphocytes, smooth muscle cells and endothelial cells, a variety of biological effects mediated by the elastin-laminin receptor which has been demonstrated to be present on the membrane of these cells. The transduction pathway of the ELR receptor involves the activation of phospholipase C (PLC) by a pertussis toxin sensitive G-protein. PLC induces the production of inositol trisphosphate (IP3) leading to the increase of the intracellular free calcium on one hand, and of diacylglycerol (DAG) which stimulates the translocation to the membrane of PKC leading to the phosphorylation of members of the MAPK family, such as p42/p44 MAPK. Considering the multiple biological effects of ELR the elucidation of the complexity of the signaling pathways will help to better modulate it, mainly in pathological situations such as atherosclerosis.
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PMID:[The elastin-laminin receptor]. 1172 28

A hallmark of vascular smooth muscle cells (VSMCs) is their dynamic ability to assemble and disassemble contractile proteins into sarcomeric units depending upon their phenotypic state. This phenotypic plasticity plays an important role during vascular development and in obstructive vascular disease. Previously, we showed that the Elastin gene product, tropoelastin, activates myofibrillar organization of VSMCs. Recently, others have suggested that elastin does not have a direct signaling role but rather binds to and alters the interactions of other matrix proteins with their cognate receptors or disrupts the binding of growth factors and cytokines. In contrast, we provide evidence that tropoelastin directly regulates contractile organization of VSMCs. First, we show that a discrete domain within tropoelastin, VGVAPG, induces myofibrillogenesis in a time- and dose-dependent fashion. We confirm specificity using a closely related control peptide that fails to stimulate actin stress fiber formation. Second, the activity of VGVAPG is not affected by the presence or absence of other serum or matrix components. Third, both the elastin hexapeptide and tropoelastin stimulate actin polymerization through a common pertussis toxin-sensitive G protein pathway that activates RhoA-GTPase and results in the conversion of G to F actin. Collectively, these data support a model whereby the elastin gene product, signaling through the VGVAPG domain, directly induces VSMC myofibrillogenesis.
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PMID:Elastin induces myofibrillogenesis via a specific domain, VGVAPG. 1461 88

Elastin peptides (EPs) produced during cancer progression bind to the elastin binding protein (EBP) found at the surface of dermal fibroblasts, leading to the expression of collagenase-1 gene. The production of this enzyme involved in stromal reaction is caused by the sustained activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway via cAMP/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K). However, the mechanism of these signaling events remains unknown. We show that kappa-elastin (kappaE), a commonly used EP, induces maximum phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)1/2 and ERK1/2 after 30 min. The simultaneous inhibition of PKA and PI3K, by N-(2-(p-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide (H89) and 2-(4-morpholynil)-8-phenyl-4H-1-bemzopyran-4-one (LY294002), respectively, blocked MEK1/2 and ERK1/2 phosphorylation, as did lactose, an EBP antagonist. kappaE induced Raf-1 phosphorylation and activation in a PI3K-dependent manner. In our system, the PI3K p110gamma is expressed and activated by betagamma-derived subunits from a pertussis toxin-sensitive G protein after fibroblast stimulation. Pertussis toxin also blocks the Raf-1/MEK1/2/ERK1/2 phosphorylation cascade. In addition, we found that B-Raf is expressed in dermal fibroblasts and activated in a PKA-dependent manner after kappaE treatment, thereby integrating PKA signals to MEK1/2. It is noteworthy that Ras involvement was excluded because ERK1/2 activation by kappaE was not blocked in RasN17-transfected fibroblasts. Together, our results identify a novel Ras-independent ERK1/2 activation system in which p110gamma/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. Thus, p110gamma and B-Raf seem to be important modulators of dermal fibroblasts physiology and should now qualify as therapeutic targets in strategies aiming at limiting elastin degradation contribution to cancer progression.
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PMID:Elastin peptides activate extracellular signal-regulated kinase 1/2 via a Ras-independent mechanism requiring both p110gamma/Raf-1 and protein kinase A/B-Raf signaling in human skin fibroblasts. 1565 54


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