Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q15004 (PAF)
 2,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have attempted to determine whether interleukin-5 (IL-5), a cytokine that selectively affects eosinophil (as opposed to neutrophil) differentiation and activation, also modulates eosinophil migrational responses. Using a modified Boyden chemotaxis assay, IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) gave a weak locomotory response for eosinophils from normal nonatopic subjects (optimal at 10(-11), 10(-8), and 10(-9) mol/L, respectively), but not for eosinophils from subjects with an eosinophilia associated with asthma and/or allergic rhinitis. In contrast, IL-5 and IL-3 had no effect on neutrophils, while GM-CSF was chemotactic for neutrophils over a limited concentration range, optimal at 10(-8) mol/L. When eosinophils from normal subjects were incubated with IL-5 (10(-9) mol/L), the locomotory response to platelet-activating factor (PAF; 10(-8) mol/L, P less than .05), leukotriene B4 (LTB4; 10(-6) mol/L, P less than .01), and N-formyl-methionyl-leucyl-phenylalanine (FMLP; 10(-8) mol/L, P less than .01) was significantly enhanced. The percentage enhancement of eosinophil locomotion by IL-5 was greater for eosinophils from normal as compared with subjects with an eosinophilia associated with asthma (P less than .05 for PAF and LTB4; P less than .01 for FMLP). Preincubation of eosinophils from normal subjects with IL-5 (10(-9) mol/L) attenuated the subsequent locomotory response to IL-5 (10(-12) and 10(-11) mol/L, P less than .05). Therefore, the observed refractoriness of eosinophils from eosinophilic subjects to both directional migratory and priming effects of IL-5 in vitro, may reflect a deactivation process resulting from prior exposure in vivo. The selective priming of eosinophil but not neutrophil locomotion by IL-5 suggests that this cytokine may play a significant role in the preferential accumulation of eosinophils at sites of allergic inflammation.
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PMID:Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects. 131 89

The neuropeptide alpha-melanocyte stimulating hormone [alpha-MSH(1-13)] occurs in the pituitary, brain, skin and other tissues and receptors for this molecule are likewise widespread. In previous research, this tridecapeptide, which shares its amino acid sequence with ACTH(1-13), was shown to have both potent antipyretic activity and a role in the endogenous control of the febrile response. alpha-MSH(1-13) and its COOH-terminal tripeptide were subsequently found to inhibit inflammation induced by general stimuli such as topical application of an irritant. The aim in the present experiments was to determine if these peptides can inhibit acute inflammatory responses induced in mice by injection of individual cytokines, endogenous pyrogen (EP), a natural cytokine mixture, and other mediators of inflammation. Inflammation induced in the mouse ear by rIL-1 beta, rIL-6 or rTNF-alpha was inhibited by alpha-MSH and a D-valine-substituted analog of alpha-MSH(11-13) whereas substantial doses of alpha-MSH(1-13) did not alter inflammation induced by LTB4, PAF and IL-8. Both peptides inhibited edema caused in the mouse paw by local injection of EP. The results indicate that alpha-MSH molecules antagonize the actions of certain cytokine mediators of inflammation, consistent with previous observations of anti-cytokine activity of these peptides. Failure to inhibit edema caused by LTB4, PAF and IL-8 suggests that, in inflammation induced by general stimuli, such as EP, the peptides act prior to the release of these mediators of the inflammatory response. Because of the anticytokine/anti-inflammatory actions of the alpha-MSH molecules they may be useful in understanding the cytokine network and for treatment of inflammatory diseases.
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PMID:Alpha-MSH peptides inhibit acute inflammation induced in mice by rIL-1 beta, rIL-6, rTNF-alpha and endogenous pyrogen but not that caused by LTB4, PAF and rIL-8. 132 96

Infiltration of glomerular mesangium by monocytes/macrophages is a prominent pathologic finding in many forms of glomerulonephritis (GN). While the mechanism(s) by which infiltration occurs is incompletely understood, monocyte adhesion to glomerular endothelial cells, provoked by inflammatory mediators, appears to be an important early step. In the present study, we assessed the influence of chemotactic peptides (C5a) and lipids (LTB4 and PAF) on adhesion of human monocytes and mesangial cells, to determine if mesangial cells (glomerular pericytes with smooth muscle properties) represent potential targets for adhesion of chemoattractant-activated monocytes following their diapedesis from the intravascular space. C5a and LTB4 provoked rapid (onset less than 1 min) monocyte-mesangial cell adhesion at nanomolar concentrations via actions with monocytes, while PAF was less potent in this regard. Monoclonal antibodies (mAb) were used to define the monocyte and mesangial cell adhesion molecules involved in these interactions. C5a- and LTB4-induced monocyte adhesion was inhibited (approximately 54%) by mAb against the common beta CD18 subunit of CD11/CD18 leukocyte integrins, while mAb against monocyte L-selectin was without effect. MAb against unique CD11 subunits were used to determine the relative contributions of different CD11/CD18 integrins. In this regard, adhesion was inhibited by mAb against CD11b (approximately 41%), and CD11c (approximately 23%), but not CD11a. MAb against mesangial cell ICAM-1 afforded approximately 27% reduction in adhesion, while mAb against VCAM-1, E-selectin, and P-selectin were without effect. GM-CSF, a cytokine generated by monocytes and mesangial cells, also provoked CD11/CD18-dependent adhesion, and primed monocytes to the actions of chemoattractants.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chemoattractants provoke monocyte adhesion to human mesangial cells and mesangial cell injury. 132 54

Cytokines with stimulatory or inhibitory activities for vascular cells are reviewed. Directly or via humoral factors, vascular endothelial cells interact with blood cells, such as lymphocytes, neutrophils and platelets, while smooth muscle cells do so with inflammatory cells. Various cytokines, including IL-1, 6, 7, 8, GM-, G-, M-CSF, a, b-FGF, PDGF, TGF beta, PAF, PA, PAI-1, cell adhesion molecules and endothelin are produced by endothelial cells and/or smooth muscle cells, and in turn they and cytokines produced by blood cells, act as modulators of growth or function of the vascular cells under some physico-pathological states. Vascular cells, especially, endothelial cells might thus be involved in cytokine network.
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PMID:[Growth regulation of vascular cells by cytokines]. 143 63

We have examined the hypothesis that cytokines mediate the enhanced responsiveness of eosinophils to PAF in sensitized mouse skin. PAF (10 ng per site) resulted in a considerable degree of eosinophil accumulation in ovalbumin (OA)-sensitized mice but not in non-sensitized mice. Intradermal preadministration of cytokines (IL-5, IL-3 and GM-CSF) also significantly enhanced PAF-induced migration of eosinophils in a dose-dependent manner. The relative potency with which these cytokines primed cell migration was IL-5 greater than IL-3 greater than GM-CSF, however, each cytokine alone showed no direct effect. We conclude that the sensitization or the exogenous application of cytokines is capable of augmenting PAF-induced eosinophil migration in mice in vivo, and the cytokines thus elicited by sensitization may contribute to the extensive recruitment of inflammatory cells in allergic diseases.
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PMID:Sensitization primes platelet-activating factor (PAF)-induced accumulation of eosinophils in mouse skin lesions: contribution of cytokines to the response. 152 51

Injection of complete Freund's adjuvant (CFA) into the right hind paw of adrenalectomized (ADX) rats caused a lethal effect, maximal after 3 days. Treatment of animals with polyclonal sera raised against either murine recombinant (mr) IL-1 alpha or mrIL-1 beta gave significant protection, suggesting the involvement of this cytokine in the observed lethality. Death was also caused by the intravenous injection of human recombinant (hr) IL-1 beta in ADX rats. No lethality was induced by either CFA or hrIL-1 beta in sham-operated (SHO) rats. The administration of dexamethasone or the dural cyclooxygenase/lipoxygenase inhibitor BW 755c significantly protected against the lethality induced by both CFA and hrIL-1 beta. The cyclooxygenase inhibitors, indomethacin and acetylsalicyclic acid, were ineffective. WEB 2086, a PAF-acether receptor antagonist, gave partial but not significant protection. These results suggest that activation of arachidonic acid metabolism is involved in the observed lethality, with lipoxygenase metabolites as possible final effectors. These experimental models of lethalities may be useful for the in vivo evaluation of drugs interfering with the synthesis and/or biological effects of IL-1.
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PMID:Evidence that interleukin-1 and lipoxygenase metabolites mediate the lethal effect of complete Freund's adjuvant in adrenalectomized rats. 193 66

Peripheral blood mononuclear cells (PBMC) separated from patients with asthma who were sensitive to Dermatophagoides farinae (Df) were cultured in alpha-medium for 5 days at 37 degrees C in 5% CO2, in the presence or absence of 10 ng/ml of Df antigen. Eosinophils were purified from the peripheral blood of patients with eosinophilia who were not sensitive to Df. Eosinophil chemotactic activity (ECA) was tested using a modified Boyden chamber method. ECA in the supernatant of PBMC stimulated with Df antigen was detectable after 24 hrs, peaked at 72 hrs and continued throughout the experiment. ECA was not observed in the supernatant of PBMC culture from subjects who were not sensitive to Df, and negligible activity was also observed when PBMC were stimulated with an unrelated antigen. The activity was unchanged by heating at 56 degrees C for 30 min, but was inactivated at 100 degrees C for 10 min. CV-6209, a specific PAF antagonist, failed to inhibit this chemotactic activity. The molecular weight of this eosinophil chemotactic factor (ECF) was greater than 30,000 daltons as determined by an ultrafiltration study. In conclusion, these data suggest that in asthmatic patients sensitive to Dermatophagoides farinae mononuclear cells stimulated with a related antigen produce one of cytokine(s) which possess(es) ECA, and may play an important role in the recruitment of eosinophils in chronic asthma.
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PMID:[Eosinophil chemotactic activity in the supernatant of mononuclear cell culture stimulated with specific antigen]. 206 10

The ability of PCA 4248 [2-(phenylthio)ethyl-5-methoxycarbonyl- 2,4,6-trimethyl-1,4-dihydropyridine-3-carboxylate] to block PAF-induced systemic hypotension and protein-rich plasma extravasation in rats, and PAF-induced death in mice, was tested. These studies were complemented with experiments using soluble aggregates of immunoglobulin G (A-IgG), bacterial endotoxin and the cytokine tumor necrosis factor as putative inducers of the generation of endogenous PAF. Significant inhibition of PAF-induced systemic hypotension was observed with i.v. PCA 4248 at doses of 0.3 to 1 mg/kg (IC50 value, 0.45 mg/kg, with PAF 0.33 micrograms/kg). Reversal of the hypotension was rapidly observed when PCA 4248 was administered after PAF. The extravasation induced by 1 microgram/kg PAF was also blocked by PCA 4248 (IC50 value, 0.36 mg/kg). Inhibition of the extravasation induced by A-IgG and endotoxin was also provided by PCA 4248 at the dose of 1 mg/kg, and lasted for at least 1 hr in the experiments carried out with endotoxin, which caused extravasation with a temporal pattern more protracted than that of PAF and A-IgG. Intradermal extravasation induced by PAF reached a maximum at 30 min after injection, and was also inhibited by PCA 4248. In contrast, PCA 4248 caused a less remarkable, but statistically significant reduction of the intradermal extravasation caused by tumor necrosis factor. Pretreatment of mice with an oral dose of 30 mg/kg PCA 4248, 5 min before challenge with PAF (LD84 = 80 micrograms/kg PAF, i.v.) increased the survival rate from 16% to 68%. These data indicate that compounds containing a 1,4-dihydropyridine structure can antagonize PAF effects on experimental animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological actions of PCA 4248, a new platelet-activating factor receptor antagonist: in vivo studies. 217 Jun 26

The present study investigated in vitro the qualitative and quantitative neutrophil function-activating properties of the most important non-cytokine participants in the acute inflammatory cell response. Apart from the results obtained with leukotriene (LT) D4, similar qualitative relationships were found for the several mediators tested regarding effects on neutrophil migration and aggregation. Thus, LTB4, PAF-acether and zymosan-activated serum all activated both functions, while f-Met-Leu-Phe had no effect. In all cases, the half-maximal eliciting concentration (EC50) for induction of chemotaxis was much lower than for aggregation, indicating that high and low receptor affinity responses were being studied, respectively. LTD4 induced modest aggregation, but was virtually without effect on migration. Using PAF-acether as stimulus, the mechanism of aggregation was studied in more detail. The results indicate that LTB4, PAF-acether, the complement-split products C5a/C5a desArg, and perhaps LTD4, may play a role as stimulants of neutrophil functions in inflammatory processes in vivo.
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PMID:Effects of proinflammatory mediators on canine neutrophil chemotaxis and aggregation. 239 62

The catastrophe theory evolved by Thom and Zeeman proposes a mathematical definition for the abrupt or 'catastrophic' changes that can suddenly occur in normally well-ordered and smooth-running systems. We have integrated this theory with our own PAF/cytokine feedback network hypothesis to explain the control and dysfunction of the inflammatory response. This process involves the activation of cells and factors such as proteases, and is coordinated by mediators such as PAF, cytokines and growth factors, minute amounts of which can prime cells to respond in an enhanced manner to subsequent agonistic stimuli. PAF and certain cytokines also possess the unique property of being able to induce the release of each other and their own generation in vivo. This 'singularity' may enable a self-generating feedback network to become established. The priming ability of these mediators indicates the extreme sensitivity of the inflammatory process and importance of a homeostatic equilibrium between the vectors involved in the priming and feedback processes and internal suppressive mechanisms. In pathological conditions, one can consider the phenomenon of PAF and cytokine autogeneration as a 'fold' in the feedback network and an expression of the singularity characteristic of the catastrophe hypothesis. This may lead to systemic toxicity and microcirculatory collapse, a characteristic feature of shock, sepsis, asthma, ischemia and graft rejection. A combination of drugs antagonizing the various feedback components may inhibit this catastrophic process and thus provide more successful therapy of these conditions.
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PMID:PAF/cytokine auto-generated feedback networks in microvascular immune injury: consequences in shock, ischemia and graft rejection. 251 89


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