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PubMed2004

Interleukin-5, interleukin-3 and granulocyte-macrophage colony-stimulating factor prime actin-polymerization in human eosinophils: a study with hypodense and normodense eosinophils from patients with atopic dermatitis.

Characteristic features of atopic diseases (AD) are immigration and local activation of eosinophils. Reorganization of the cytoskeleton modulates the function of leukocytes and is a prerequisite for the motility response. In this work, the regulation of actin polymerization has been investigated by flow cytometry using NBD-phallacidin and right angle light scatter measurements in purified eosinophils isolated from patients with atopic dermatitis and normal individuals. Stimulation of eosinophils with chemotaxins such as complement fragment C5a (C5a), CC chemokine RANTES/ CCL5 and platelet activating factor (PAF) induced a reversible polymerization of actin. Normodense eosinophils purified from patients with AD showed a decreased chemotaxin-induced actin response as compared to normodense eosinophils from healthy subjects and hypodense eosinophils from patients. Stimulation of eosinophils with Th2-cytokines such as interleukin-3 (IL-3), interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF) did not exert a significant effect on actin polymerization. However, pretreatment with IL-3, IL-5 or GM-CSF potentiated the chemotaxin-induced actin polymerization and graded the differential responsiveness between normodense and hypodense eosinophils. We demonstrate a different actin responsiveness in eosinophils from atopic patients and healthy subjects which could be overcome by modulating effects of Th2-cytokines.

Actins↗
PubMedDate not supplied

[Familial Mediterranean Fever (FMF): from diagnosis to treatment].

Familial Mediterranean Fever (FMF), also known as paroxysmal polyserositis, is an autosomal recessive disease affecting mainly Mediterranean populations (Jews, Armenians, Arabs, Turks). It is characterised by recurrent crises of fever and serosal inflammation, leading to abdominal, thoracic or articular pain. Erysipela-like erythema affecting mainly feet and legs and effort-induced myalgia are less frequently encountered symptoms. The major complication of FMF is the development of renal amyloidosis. Standard laboratory tests of FMF patients are non-informative, except for the high sedimentation rate and white blood cell count, but during and immediately after crises, diminished albumin concentrations and elevated fibrinogen, C-reactive protein, beta2 and alpha2 M globulins, haptoglobin and lipoprotein concentrations are noted. Studies have measured immunoglobulin (Ig) levels in the sera of FMF patients and found elevated levels of IgA, IgM, IgG, and IgD in 23%, 13%, 17% and 13%, respectively. FMF crises are characterised by a massive influx of polymorphonuclear leukocytes into the inflamed regions. Moreover, the peritoneal fluid of FMF patients contains abnormally low levels of the inhibitor of complement fragment C5a and interleukin 8. Failure to suppress inflammatory response to C5a may explain the typical inflammatory FMF crises. The MEFV (for MEditerranean FeVer) gene responsible for the disease has been identified on 16p13.3. It is composed of 10 exons and spans approximately 14 Kb of genomic DNA. More than 35 mutations have so far been identified. The most frequent are M694V, M694I, M680I, V726A and E148Q. The M694V mutation is the most frequent mutation in the various ethnic groups considered, although its frequency varies from group to group. The V726A mutation is observed mainly among Ashkenazi and Iraqi Jews, Druzes and Armenians, and the M680I among Armenians and Turks. M694I and A744S seem specific to Arab populations, and R761H is frequently found in Lebanese FMF patients. The M694V mutation is often correlated with severe phenotypes, mainly in the homozygous state. It has been specifically correlated with arthritis, pleuritis and especially amyloidosis. Patients with other mutations in the 694 and 680 codons can also have severe phenotypes. The V726A mutation, although identified in FMF patients with a relatively mild phenotype, has also been detected in patients with renal amyloidosis. E148Q is often associated with a mild phenotype, and whether it is even a polymorphism has been questioned. The MEFV gene codes for a protein that was respectively called pyrin and marenostrin by the French and international consortia that simultaneously identified the gene. Its function is still not determined, but it was recently colocalised with microtubules and actin filaments in the cytoplasm. It contains a death domain called PYD (Pyrin Domain), usually associated with proteins involved in apoptosis. Some genes have been tested to assess their possible modifying effects on clinical features of FMF. The alpha/alpha genotype of the serum amyloid A or SAA1 gene is associated with an increased risk of amyloidosis in FMF patients, especially in patients homozygous for M694V, whereas the MICA (Major Histocompatibility Complex, MHC class-I-chain-related type A) gene seems to have an effect on disease course but not its clinical manifestations. The most effective treatment for FMF patients is colchicine, which should be taken regularly on a life-long basis. It decreases the frequency and severity of crises and prevents renal amyloidosis.

Adult↗
PubMed1992

Effect of nerve growth factor on the release of inflammatory mediators by mature human basophils.

Nerve growth factor (NGF) is a neurotrophic cytokine known to regulate the survival and function of peripheral and central neuronal cells. Recently, the spectrum of action could be extended to non-neuronal cell types such as rat mast cells and human B lymphocytes. The present study shows that NGF affects the function of mature human basophils isolated from the peripheral blood of healthy donors. Both murine NGF 7S and recombinant human NGF beta enhance histamine release and strongly modulate the formation of lipid mediators by basophils in response to various stimuli. This priming effect of NGF on basophils occurs rapidly within 10 to 15 minutes of preincubation, is dose-dependent, and requires similarly low concentrations (1 to 40 pmol/L) of human NGF beta as the induction of neurite outgrowth in ganglion cells. Cell fractionation studies indicate that NGF acts directly on human basophils without an involvement of other cell types, suggesting the presence of high-affinity NGF receptors on basophils. NGF by itself (up to 4 nmol/L of human NGF beta) does not induce the release of inflammatory mediators directly. The effect of human NGF on basophil mediator release is similar to that of the hematopoietic growth factors interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor. The present study further demonstrates that NGF acts as a pleiotropic cytokine at the interface between the nervous and the immune system, and that NGF may be involved in inflammatory processes and hypersensitivity reactions.

Basophils↗
PubMed1992

The effect of cytokines and chemotactic agonists on the migration of T lymphocytes into skin.

The migration of lymphocytes and neutrophils into skin sites stimulated with chemotactic agonists or with cytokines known to induce leucocyte-endothelial adhesion molecules was examined in sheep. Lymphocytes, collected from efferent prefemoral lymph, labelled in vitro with [111In]oxine and reinjected intravenously, migrated in large numbers into delayed-type hypersensitivity (DTH) reactions elicited by purified protein derivative (PPD) and into sites stimulated with tumour necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma). In contrast, interleukin (IL)-1 alpha, a potent inducer of endothelial leucocyte adhesion molecule-1 (ELAM-1), caused moderate accumulation of [111In]lymphocytes at concentrations that induced intense accumulation of 111In-labelled neutrophils. The chemotactic agonists IL-8 and zymosan-activated plasma (ZAP) caused accumulation of very large numbers of neutrophils but only small numbers of lymphocytes, whereas platelet-activating factor (PAF) and leukotriene B4 (LTB4) failed to recruit lymphocytes into skin. IFN-gamma was the only mediator to recruit lymphocytes in preference to neutrophils into skin. The results suggest that those lymphocyte chemotactic agonists which lack the ability to induce adhesion molecules on endothelium play only a minor role in directing migration of lymphocytes into skin. Immunohistological examination of skin lesions confirmed the findings of studies with 111In-labelled lymphocytes and indicated that there was a tendency for CD4+ cells to outnumber CD8+ cells in infiltrates induced by all mediators. In contrast to the elevated numbers of T19+ subset of T-cell receptor (TcR+) gamma delta cells present in DTH reactions, none of the mediators induced migration of T19+ cells into skin.

Animals↗
PubMed1991

[Current knowledge of the mechanism of neutrophil granulocyte and macrophage activation for the formation of superoxide anions and of H2O2 and for the causes of defects in the NADPH-oxidase enzyme system involved].

By the binding of activators (f.e. complement factor C5a, leukotriene B4) to receptors of neutrophil granulocytes an activation of a GTP-binding protein is induced, that increases the activity of the phospholipase C in the membrane and thereby the liberation of inositol-1,4,5-phosphate (IP) and of diacylglycerol (DG). The IP effects the liberation of Ca from intracellular stores and an increase in the concentration of Ca-ions in the cytosol. The DG induces an activation of the phosphokinase C near the membrane, that phosphorylates a cytosolic protein, which takes part in the formation of the NADPH-oxidase. The mentioned reactions induce in the membrane the construction of the NADPH-oxidase from a NADPH-binding protein, a flavoprotein, a cytochrome b 558 and from 4 cytosolic proteins. When phagolysosomes are formed, the NADPH-oxidase is part of the membrane, so bactericidal superoxide-anions can be introduced in these. In the chronic granulomatous disease defects in the formation of cytochrome b or of 2 cytosolic proteins exist.

Anions↗
PubMed1991

Intravascular IL-8. Inhibitor of polymorphonuclear leukocyte accumulation at sites of acute inflammation.

IL-8 has been characterized primarily as a polymorphonuclear leukocyte (PMN) chemoattractant and proinflammatory mediator. Recently, we have reported that [Ala-IL-8]77 is secreted by activated cultured human endothelial cells and can function as a potent inhibitor of PMN adhesion to these monolayers. The pathophysiologic relevance of this in vitro observation was examined by determining the effects of intravascular or extravascular administration of IL-8 on PMN emigration at sites of acute inflammation in the skin of NZW rabbits. An i.v. bolus of [Ala-IL-8]77 (12 micrograms/kg) produced a marked and selective reduction of circulating PMN within 3 min, which returned toward preinjection levels within 30 min, and subsequently exceeded this level. A similar response was observed for circulating radiolabeled PMN, and gamma-scintigraphy determined that the lungs were the primary site of leukosequestration. During the 30- to 150-min interval after i.v. infusion of [Ala-IL-8]77, PMN emigration into acute inflammatory sites, elicited by various chemoattractants or cytokines, was significantly reduced, as judged histologically and quantitated with 51Cr-labeled PMN and myeloperoxidase measurements. Intravenous administration of [Ser-IL-8]72 yielded similar results. This inhibitory effect of i.v. IL-8 was transient and reinducible and did not reflect a suppression of the responsiveness of circulating PMN to chemoattractants. Intradermal injections of [Ala-IL-8]77 or [Ser-IL-8]72 induced dose-dependent PMN accumulation, which also was significantly reduced by i.v. administration of either form of IL-8. These results indicate that i.v. IL-8 can function as a PMN-directed leukocyte adhesion inhibitor and suggest that local secretion of IL-8 by activated endothelium may differentially modulate leukocyte-endothelial interactions at sites of acute inflammation.

Animals↗
PubMed1991

Inflammatory edema induced by interactions between IL-1 and the neuropeptide calcitonin gene-related peptide.

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator with a long duration of action. CGRP is widely distributed and is present in perivascular nerves of tissues that include skin and the synovium. In this study we have investigated the possibility that CGRP can modulate the inflammatory actions of the cytokine IL-1 by using an inflammatory model in rabbit skin. The intradermal injection of IL-1 (1.4 x 10(-14) mol/site) alone stimulated little edema formation. However, when IL-1 was injected with CGRP (10(-11) mol/site), a highly significant edema was observed, and neutrophil accumulation induced by IL-1 was potentiated. These results suggest that the action of IL-1 as a potent mediator of increased microvascular permeability is only observed when skin blood flow is increased in this model. This was confirmed by experiments in which PGE2 (3 x 10(-9) mol/site) at a dose with a similar duration of vasodilator action as CGRP (10(-11) mol/site) also potentiated edema induced by IL-1. Further experiments investigated the mechanism by which IL-1 increased microvascular permeability. Edema induced by IL-1 was dependent on de novo protein synthesis and the presence of circulating neutrophils. However, selective platelet-activating factor and histamine H1 antagonists had no inhibitory effect on this response. Thus it appears that when a microvascular bed is dilated by the long-lasting vasodilator CGRP, edema induced by IL-1 is clearly observed. These results highlight a potentially important synergistic interaction between cytokines and neuropeptides in inflammation.

Animals↗
PubMed1990

Priming of the human neutrophil respiratory burst by granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha involves regulation at a post-cell surface receptor level. Enhancement of the effect of agents which directly activate G proteins.

Over the last few years, several studies showing that production of superoxide by neutrophils in response to chemotactic factors such as FMLP is enhanced after preincubation of the cells with granulocyte-macrophage (GM)-CSF or TNF-alpha have been published. Subsequent reports have indicated that this effect of the cytokines may be mediated by modulation of the number and/or affinity of surface receptors for FMLP. In the present study we have investigated the effect of preincubation with GM-CSF and TNF-alpha on the oxidative burst induced by sodium fluoride and guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S)-agents which directly activate guanine-nucleotide binding proteins in neutrophils. Pretreatment of neutrophils with either GM-CSF or TNF-alpha dose-dependently enhanced the production of superoxide induced by NaF, as determined by the superoxide dismutase-inhibitable reduction of ferricytochrome c. Furthermore, preincubation of neutrophils with these cytokines enhanced the production of hydrogen peroxide induced by GTP gamma S in electroporated neutrophils. Because both NaF and GTP gamma S directly activate G proteins independently of external receptor-G protein interaction, these results imply that both GM-CSF and TNF-alpha alter the neutrophil signal transduction pathway in response to subsequent agonists independently of a modulation in the expression of the cell surface receptors for such agonists.

Complement C5a↗
PubMed1990

[Allergic reaction and vascular permeability].

The allergic reaction is characterized by an inflammatory phenomenon that comprises a cellular aspect and a vascular aspect. The vascular aspect is linked to the production of several mediators able to induce a vascular hyperpermeability. Among these mediators it is possible to find histamine, prostaglandins, leukotrienes, PAF, neuromediators, kinins, anaphylatoxins.

Animals↗