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Biomedical subjects

G Marone

Publications and source records attributed to G Marone.

At least 19 recordsLinked to original sources
PubMed2004

Differential modulation of mediator release from human basophils and mast cells by mizolastine.

BACKGROUND: Basophils and mast cells play a major role in the pathogenesis of allergic disorders by releasing several proinflammatory mediators. Some histamine H1 receptor antagonists exert anti-inflammatory activities by modulating mediator release from basophils and mast cells. OBJECTIVE: To study the in vitro effects of mizolastine, an H1 receptor antagonist, on the release of eicosanoids, histamine and IL-4 from human basophils and lung mast cells. METHODS AND RESULTS: Mizolastine (10(-7)-10(-5) M) concentration-dependently inhibited the release of cysteinyl leukotriene C4 from anti-IgE-stimulated basophils (IC(50): 3.85+/-0.28 microM) and mast cells (IC(50): 3.92+/-0.41 microM). The same concentrations of mizolastine did not affect anti-IgE-induced prostaglandin D2 release from lung mast cells. In contrast, mizolastine enhanced up to 80% IgE-mediated histamine release (EC(50): 4.63+/-0.14 microM) from basophils, but not from mast cells and it significantly potentiated IL-4 release from basophils induced by anti-IgE. Mizolastine did not affect histamine release from basophils induced by formyl peptide, whereas it inhibited cysteinyl leukotriene C4 release (IC(50): 1.86+/-0.24 microM). Blockade of cytosolic phospholipase A2 and arachidonic acid mobilization by pyrrolidine-1 did not alter the effect of mizolastine on histamine release from basophils, thereby excluding accumulation of arachidonic acid metabolic intermediates as the cause of this effect. Mizolastine did not influence anti-IgE-induced activation of extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2) in human basophils. CONCLUSIONS: Mizolastine efficiently inhibits LTC4 synthesis in human basophils and mast cells presumably by interfering with 5-lipoxygenase. In contrast, it enhances histamine and IL-4 release only from anti-IgE-stimulated basophils. Therefore, mizolastine differentially regulates the production of mediators from basophils and mast cells in a cell- and stimulus-specific fashion.

Antibodies, Anti-Idiotypic↗
PubMed2003

In vitro effects of ultraviolet A on histamine release from human basophils.

BACKGROUND: As long-wave ultraviolet (UV) radiation penetrates the dermis, connective tissue cellular components and circulating blood cells can be possible targets for solar UVA. Basophils, involved in the effector phase of the inflammatory response, play a part in skin diseases such as chronic urticaria, psoriasis, atopic dermatitis, fixed drug eruption, allergic contact dermatitis, urticaria pigmentosa, systemic sclerosis and bullous pemphigoid. OBJECTIVE: The evaluation of the in vitro effect of UVA on histamine release from human basophils. METHODS: Basophils from healthy human volunteers were irradiated, respectively, with UVA at doses of 2.5, 5, 7.5, 10, 20 and 50 J/cm2 and then incubated with an anti-IgE serum. A fluorimetric technique was employed to determine histamine release from samples: (i) incubated with 2% HClO4 (complete lysis of basophils); (ii) irradiated with increasing doses of UVA; and (iii) unirradiated (controls). RESULTS: Histamine release was: 100% for HClO4 incubated basophils, 30% for unirradiated and anti-IgE incubated cells (controls) and 27%, 24%, 34%, 41%, 60% and 70% for basophils irradiated with UVA doses, respectively, of 2.5, 5, 7.5, 10, 20 and 50 J/cm2 and incubated with anti-IgE. Histamine releasability from irradiated samples was statistically significant (P < 0.05), in comparison with controls, at UVA doses equal to 5, 10, 20 and 50 J/cm2. CONCLUSIONS: UVA exerts, at least in vitro, a biphasic dose-dependent action on histamine release from human basophils incubated with an anti-IgE serum: at the lowest irradiation doses (< 5 J/cm2) it exerts an inhibitory effect and at the highest doses (> or = 10 J/cm2) histamine release increases significantly.

Basophils↗
PubMed2001

Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors.

Increasing evidence suggests that a continuous release of histamine from mast cells occurs in the airways of asthmatic patients and that histamine may modulate functions of other inflammatory cells such as macrophages. In the present study histamine (10(-9)-10(-6) M) increased in a concentration-dependent fashion the basal release of beta-glucuronidase (EC(50) = 8.2 +/- 3.5 x 10(-9) M) and IL-6 (EC(50) = 9.3 +/- 2.9 x 10(-8) M) from human lung macrophages. Enhancement of beta-glucuronidase release induced by histamine was evident after 30 min and peaked at 90 min, whereas that of IL-6 required 2-6 h of incubation. These effects were reproduced by the H(1) agonist (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptane carboxamide but not by the H(2) agonist dimaprit. Furthermore, histamine induced a concentration-dependent increase of intracellular Ca(2+) concentrations ([Ca(2+)](i)) that followed three types of response, one characterized by a rapid increase, a second in which [Ca(2+)](i) displays a slow but progressive increase, and a third characterized by an oscillatory pattern. Histamine-induced beta-glucuronidase and IL-6 release and [Ca(2+)](i) elevation were inhibited by the selective H(1) antagonist fexofenadine (10(-7)-10(-4) M), but not by the H(2) antagonist ranitidine. Inhibition of histamine-induced beta-glucuronidase and IL-6 release by fexofenadine was concentration dependent and displayed the characteristics of a competitive antagonism (K(d) = 89 nM). These data demonstrate that histamine induces exocytosis and IL-6 production from human macrophages by activating H(1) receptor and by increasing [Ca(2+)](i) and they suggest that histamine may play a relevant role in the long-term sustainment of allergic inflammation in the airways.

Calcium↗
PubMed2001

Diagnostic criteria and classification of mastocytosis: a consensus proposal.

The term 'mastocytosis' denotes a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells (MC) in one or more organ systems. Over the last 20 years, there has been an evolution in accepted classification systems for this disease. In light of such developments and novel useful markers, it seems appropriate now to re-evaluate and update the classification of mastocytosis. Here, we propose criteria to delineate categories of mastocytosis together with an updated consensus classification system. In this proposal, the diagnosis cutaneous mastocytosis (CM) is based on typical clinical and histological skin lesions and absence of definitive signs (criteria) of systemic involvement. Most patients with CM are children and present with maculopapular cutaneous mastocytosis (=urticaria pigmentosa, UP). Other less frequent forms of CM are diffuse cutaneous mastocytosis (DCM) and mastocytoma of skin. Systemic mastocytosis (SM) is commonly seen in adults and defined by multifocal histological lesions in the bone marrow (affected almost invariably) or other extracutaneous organs (major criteria) together with cytological and biochemical signs (minor criteria) of systemic disease (SM-criteria). SM is further divided into the following categories: indolent systemic mastocytosis (ISM), SM with an associated clonal hematologic non-mast cell lineage disease (AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL). Patients with ISM usually have maculopapular skin lesions and a good prognosis. In the group with associated hematologic disease, the AHNMD should be classified according to FAB/WHO criteria. ASM is characterized by impaired organ-function due to infiltration of the bone marrow, liver, spleen, GI-tract, or skeletal system, by pathologic MC. MCL is a 'high-grade' leukemic disease defined by increased numbers of MC in bone marrow smears (>or=20%) and peripheral blood, absence of skin lesions, multiorgan failure, and a short survival. In typical cases, circulating MC amount to >or=10% of leukocytes (classical form of MCL). Mast cell sarcoma is a unifocal tumor that consists of atypical MC and shows a destructive growth without (primary) systemic involvement. This high-grade malignant MC disease has to be distinguished from a localized benign mastocytoma in either extracutaneous organs (=extracutaneous mastocytoma) or skin. Depending on the clinical course of mastocytosis and development of an AHNMD, patients can shift from one category of MC disease into another. In all categories, mediator-related symptoms may occur and may represent a serious clinical problem. All categories of mastocytosis should be distinctively separated from reactive MC hyperplasia, MC activation syndromes, and a more or less pronounced increase in MC in myelogenous malignancies other than mastocytosis. Criteria proposed in this article should be helpful in this regard.

Adult↗
PubMed2001

Treatment of mastocytosis: pharmacologic basis and current concepts.

Mastocytosis is a rare, heterogeneous disorder characterized by a marked increase in mast cell density in various tissues. Mast cells from different human tissues are heterogeneous. So far, there is no cure for systemic mastocytosis. Conventional therapy is based on agents that antagonize mediators released from mast cells, drugs that inhibit the release of mediators and agents that modulate mast cell proliferation. This pharmacologic approach is satisfactory in the majority of patients with indolent mastocytosis. At the beginning of the new millennium, the therapy of severe forms of aggressive mastocytosis remains a challenge for students of this intriguing disorder.

Adenylyl Cyclases↗
PubMed2001

Human mast cells and basophils in HIV-1 infection.

Mast cells and basophils (FcvarepsilonRI(+) cells) are classically involved in allergic disorders. HIV-1 glycoprotein gp120 acts as a viral superantigen by interacting with the heavy chain, variable 3 (V(H)3) region of IgE to induce cytokine release from FcvarepsilonRI(+) cells. The chemokine receptors CCR3 and CXCR4, co-receptors for HIV-1, are expressed by FcvarepsilonRI(+) cells. Via its interaction with CCR3, HIV-1 transactivation (Tat) protein is a potent chemoattractant for FcvarepsilonRI(+) cells. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor. There is some evidence that human FcvarepsilonRI(+) cells could be infected in vitro by M-tropic HIV-1 strains.

Basophils↗
PubMed2001

Role of human FcepsilonRI+ cells in HIV-1 infection.

Enhanced serum IgE levels in adults and children with HIV-1 infection could be a marker of poor prognosis. HIV-1 infection is believed to involve a switch toward a "TH2-like" cytokine pattern. HIV-1 gp120 from different clades is a potent stimulus for histamine release from human basophils and mast cells. Gp120 also induces IL-4 and IL-13 synthesis from basophils. It functions as a viral superantigen by interacting with the VH3 region of IgE to induce mediator release from human FcepsilonRI+ cells. The chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES, is expressed by basophils and lung mast cells. By interacting with the CCR3 receptor on FcepsilonRI+ cells, HIV-1 Tat protein is a potent chemoattractant for basophils and lung mast cells. Tat protein also induces IL-4 and IL-13 release from basophils. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor, a co-receptor of HIV-1 infection. Extracellular Tat affects the directional migration of human FcepsilonRI+ cells, CCR3 expression and TH2 cytokines release. We have shown that HIV-1 proteins gp120 and Tat trigger the release of cytokines critical for TH2 polarization from FcepsilonRI+ cells through two distinct mechanisms. In addition, Tat upregulates the beta-chemokine receptor CCR3, making FcepsilonRI+ cells more susceptible to infection with CCR3 tropic HIV-1 isolates.

Antibodies, Monoclonal↗
PubMed2001

Dysregulation of the IgE/Fc epsilon RI network in HIV-1 infection.

Serum IgE levels are increased in adults and children with HIV-1 infection and could be a marker of poor prognosis. Allergic reactions and adverse reactions to drugs are also increased in HIV-1-infected individuals. An imbalance between a T(H)1-like and a T(H)2-like cytokine profile has been documented in HIV-1 infection. We have found that HIV-1 gp120 from different clades is a potent stimulus for histamine and cytokine (IL-4 and IL-13) release from basophils. Gp120 acts as a viral superantigen, interacting with the V(H)3 region of IgE to induce mediator release from human Fc epsilon RI(+) cells. Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. By interacting with the CCR3 receptor on Fc epsilon RI(+) cells, HIV-1 Tat protein is a potent chemoattractant for human basophils and lung mast cells. Tat protein also induced IL-4 and IL-13 release from basophils. Preincubation of basophils with Tat protein upregulated the surface expression of the CCR3 receptor. Extracellular Tat can influence the directional migration of human Fc epsilon RI(+) cells, the expression of chemokine receptor CCR3, and the release of T(H)2 cytokines. Because Tat protein is actively released by HIV-1-infected cells, our results indicate a novel mechanism by which Fc epsilon RI(+) cells are rendered more susceptible to infection with CCR3-tropic HIV-1 isolates; that is, two HIV-1 proteins, gp120 and Tat, trigger the release of cytokines critical for T(H)2 polarization from Fc epsilon RI(+) cells, and Tat upregulates beta-chemokine receptor CCR3 on these cells.

HIV Infections↗
PubMed2001

Are mast cells MASTers in HIV-1 infection?

HIV-1 gp120 interacts with IgE V(H)3(+) on the surface of human basophils and mast cells (Fc epsilon RI(+) cells), acting as a viral immunoglobulin superantigen. gp120 from different clades induces mediator release from Fc epsilon RI(+) cells. gp120 also induces IL-4 and IL-13 synthesis in human basophils. The chemokine receptors CCR3 and CXCR4, which are coreceptors of HIV-1 infection, are expressed by human Fc epsilon RI(+) cells. HIV-1 Tat protein is a potent chemoattractant for basophils and lung mast cells, interacting with CCR3. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor. There is evidence that human Fc epsilon RI(+) cells could be infected in vitro by M-tropic HIV-1 strains.

Basophils↗
PubMed2000

Tat protein is an HIV-1-encoded beta-chemokine homolog that promotes migration and up-regulates CCR3 expression on human Fc epsilon RI+ cells.

Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. HIV-1 Tat protein is a potent chemoattractant for basophils and lung mast cells obtained from healthy individuals seronegative for Abs to HIV-1 and HIV-2. Tat protein induced a rapid and transient Ca(2+) influx in basophils and mast cells, analogous to beta-chemokines. Tat protein neither induced histamine release from human basophils and mast cells nor increased IL-3-stimulated histamine secretion from basophils. The chemotactic activity of Tat protein was blocked by preincubation of FcepsilonRI(+) cells with anti-CCR3 Ab. Preincubation of Tat with a mAb anti-Tat (aa 1-86) blocked the migration induced by Tat. In contrast, a mAb specific for the basic region (aa 46-60) did not inhibit the chemotactic effect of Tat protein. Tat protein or eotaxin desensitized basophils to a subsequent challenge with the autologous or the heterologous stimulus. Preincubation of basophils with Tat protein up-regulated the level of CCR3 mRNA and the surface expression of the CCR3 receptor. Tat protein is the first identified HIV-1-encoded beta-chemokine homologue that influences the directional migration of human FcepsilonRI(+) cells and the expression of surface receptor CCR3 on these cells.

Adult↗
PubMed2000

The immunoglobulin superantigen-binding site of HIV-1 gp120 activates human basophils.

OBJECTIVE: To investigate the mechanism whereby HIV-1 envelope glycoprotein gp120 from four different isolates obtained in three different countries induces proinflammatory mediator release from normal human basophils. METHODS: Histamine, cysteinyl leukotriene C4 (LTC4) and interleukin 4 (IL-4) release into the supernatant was measured in gp120-stimulated peripheral blood basophils from HIV-1 and HIV-2 negative subjects. RESULTS: The HIV glycoprotein was a potent stimulus for release of these mediators in basophils purified from donors negative for HIV-1 and HIV-2. There was also a correlation (r = 0.58; P < 0.01) between the maximum IL-4 release from basophils induced by gp120 and by anti-IgE. Basophils from which IgE had been dissociated by brief exposure to lactic acid no longer released histamine in response to gp120 and anti-IgE. Anti-IgE specifically desensitized basophils to a subsequent challenge with anti-IgE and gp120. Human monoclonal IgM carrying the VH3 domain, but not that carrying the VH6 domain, inhibited gp120-induced secretion of histamine from basophils in a concentration-dependent manner. Synthetic peptides identical to regions distant from the N- and C-termini of gp120MN inhibited its activating capacity. CONCLUSIONS: gp120 acts as a viral superantigen interacting with the VH3 domain of IgE to induce the release of preformed and de novo synthesized mediators from human cells carrying the Fc fragment Fc epsilonRI receptor.

Adult↗
PubMed2000

Secretory phospholipases A2 induce beta-glucuronidase release and IL-6 production from human lung macrophages.

Secretory phospholipases A2 (sPLA2s) are a group of extracellular enzymes that release fatty acids at the sn-2 position of phospholipids. Group IIA sPLA2 has been detected in inflammatory fluids, and its plasma level is increased in inflammatory diseases. To investigate a potential mechanism of sPLA2-induced inflammation we studied the effect of group IA (from cobra venom) and group IIA (human synovial) sPLA2s on human macrophages. Both sPLA2s induced a concentration- and Ca2+-dependent, noncytotoxic release of beta-glucuronidase (16.2 +/- 2.4% and 13.1 +/- 1.5% of the total content with groups IA and IIA, respectively). Both sPLA2s also increased the rate of secretion of IL-6 and enhanced the expression of IL-6 mRNA. Preincubation of macrophages with inhibitors of the hydrolytic activity of sPLA2 or cytosolic PLA2 did not influence the release of beta-glucuronidase. Incubation of macrophages with p-aminophenyl-mannopyranoside-BSA (mp-BSA), a ligand of the mannose receptor, also resulted in beta-glucuronidase release. However, while preincubation of macrophages with mp-BSA had no effect on beta-glucuronidase release induced by group IIA sPLA2, it enhanced that induced by group IA sPLA2. A blocking Ab anti-mannose receptor inhibited both mp-BSA- and group IIA-induced beta-glucuronidase release. Taken together, these data indicate that group IA and IIA sPLA2s activate macrophages with a mechanism independent from their enzymatic activities and probably related to the activation of the mannose receptor or sPLA2-specific receptors. The secretion of enzymes and cytokines induced by sPLA2s from human macrophages may play an important role in inflammation and tissue damage associated with the release of sPLA2s.

Aniline Compounds↗
PubMed2000

HIV-1 gp120 induces IL-4 and IL-13 release from human Fc epsilon RI+ cells through interaction with the VH3 region of IgE.

HIV-1 glycoprotein (gp) 120 from different clades is a potent stimulus for IL-4 and IL-13 release from basophils purified from healthy individuals seronegative for Abs to HIV-1 and HIV-2. IL-4 mRNA, constitutively present in basophils, was increased after stimulation by gp120 and was inhibited cyclosporin A and tacrolimus. IL-4 and IL-13 secretion from basophils activated by gp120 was not correlated. There was a correlation between the maximum gp120- and anti-IgE-induced IL-4 release from basophils. The average t1/2 gp120-induced IL-4 release was lower than for IL-13 release. Basophils from which IgE had been dissociated by brief exposure to lactic acid no longer released IL-4 in response to gp120 or to anti-IgE. The response to a mAb cross-linking the alpha-chain of high-affinity receptor for IgE (Fc epsilon RI) was unaffected by this treatment. Three human VH3+ monoclonal IgM inhibited gp120-induced secretion of IL-4 from basophils. In contrast, VH6+ monoclonal IgM did not inhibit the release of IL-4 induced by gp120. Synthetic peptides distant from the NH2 and COOH termini of gp120MN inhibited the activating property of gp120MN. These results indicate that gp120, which acts as a viral superantigen, interacts with the VH3 region of IgE to induce the release of IL-4 and IL-13 from human Fc epsilon RI+ cells.

Adult↗