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Theoharis C Theoharides - One of the best experts on this subject based on the ideXlab platform.

  • mercury induces inflammatory Mediator Release from human mast cells
    Journal of Neuroinflammation, 2010
    Co-Authors: Duraisamy Kempuraj, Shahrzad Asadi, Bodi Zhang, Akrivi Manola, Jennifer Hogan, Erika Peterson, Theoharis C Theoharides
    Abstract:

    Background: Mercury is known to be neurotoxic, but its effects on the immune system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD) have “allergic” symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl2) on human mast cell activation. Methods: Human leukemic cultured LAD2 mast cells and normal human umbilical cord blood-derived cultured mast cells (hCBMCs) were stimulated by HgCl2 (0.1-10 μM) for either 10 min for beta-hexosaminidase Release or 24 hr for measuring vascular endothelial growth factor (VEGF) and IL-6 Release by ELISA. Results: HgCl2 induced a 2-fold increase in b-hexosaminidase Release, and also significant VEGF Release at 0.1 and 1 μM (311 ± 32 pg/10 6 cells and 443 ± 143 pg/10 6 cells, respectively) from LAD2 mast cells compared to control cells (227 ± 17 pg/10 6 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 μM) to the proinflammatory neuropeptide substance P (SP, 0.1 μM) had synergestic action in inducing VEGF from LAD2 mast cells. HgCl2 also stimulated significant VEGF Release (360 ± 100 pg/10 6 cells at 1 μM, n = 5, p < 0.05) from hCBMCs compared to control cells (182 ± 57 pg/10 6 cells), and IL-6 Release (466 ± 57 pg/10 6 cells at 0.1 μM) compared to untreated cells (13 ± 25 pg/10 6 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 μM) to SP (5 μM) further increased IL-6 Release. Conclusions: HgCl2 stimulates VEGF and IL-6 Release from human mast cells. This phenomenon could disrupt the blood-brain-barrier and permit brain inflammation. As a result, the findings of the present study provide a biological mechanism for how low levels of mercury may contribute to ASD pathogenesis.

  • flavonols inhibit proinflammatory Mediator Release intracellular calcium ion levels and protein kinase c theta phosphorylation in human mast cells
    British Journal of Pharmacology, 2005
    Co-Authors: Duraisamy Kempuraj, B Madhappan, Spyridon Christodoulou, William Boucher, Jing Cao, Nikoletta Papadopoulou, Curtis L Cetrulo, Theoharis C Theoharides
    Abstract:

    Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which -- the flavonols, inhibits histamine and some cytokine Release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory Mediator Release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 microM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-alpha was inhibited by 82-93% at 100 microM quercetin and kaempferol, and 31-70% by myricetin and morin. Tryptase Release was inhibited by 79-96% at 100 microM quercetin, kampferol and myricetin, but only 39% by morin; histamine Release was inhibited 52-77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose-response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC theta). Flavonol inhibition of IgE-mediated proinflammatory Mediator Release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC theta signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases.

  • flavonols inhibit proinflammatory Mediator Release intracellular calcium ion levels and protein kinase c theta phosphorylation in human mast cells
    British Journal of Pharmacology, 2005
    Co-Authors: Duraisamy Kempuraj, B Madhappan, Spyridon Christodoulou, William Boucher, Nikoletta Papadopoulou, Curtis L Cetrulo, Theoharis C Theoharides
    Abstract:

    Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which – the flavonols, inhibits histamine and some cytokine Release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory Mediator Release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 μM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-α was inhibited by 82–93% at 100 μM quercetin and kaempferol, and 31–70% by myricetin and morin. Tryptase Release was inhibited by 79–96% at 100 μM quercetin, kampferol and myricetin, but only 39% by morin; histamine Release was inhibited 52–77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose–response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC θ). Flavonol inhibition of IgE-mediated proinflammatory Mediator Release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC θ signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases. Keywords: Cytokines, flavonols, mast cells, PKC θ, tryptase, quercetin Introduction Mast cells are important effector cells in IgE-mediated reactions by secreting histamine, chymase, tryptase, leukotrienes (LTs), prostaglandin D2 (PGD2) and several multifunctional cytokines; they include interleukin-6 (IL-6), IL-8, IL-13, tumor necrosis factor-alpha (TNF-α), stem cell factor (SCF) and many chemotactic factors (Galli, 2000; Mekori & Metcalfe, 2000). These cytokines contribute to the late-phase allergic reactions and to allergic inflammation through the recruitment of immune cells into the site of inflammation (Wedemeyer et al., 2000; Theoharides & Cochrane, 2004). Tryptase, expressed by all subsets of human mast cells and comprising up to 25% of the total intracellular proteins, has emerged as an important Mediator in allergic diseases (Shaoheng et al., 1998). Tryptase and other serine proteases are signaling molecules that cleave protease-activated surface receptor-2 (PAR-2) leading to widespread inflammation (Steinhoff et al., 2000; Cottrell et al., 2003). Calcium influx is necessary for mast cell Mediator secretion (Kimata et al., 2000b) and PAR-2 activation has also been associated with a brisk increase in intracellular calcium concentration (Dery et al., 1998). The limited number of mast cells obtained from normal human tissues has led to increasing use of human umbilical cord blood-derived cultured mast cells (hCBMCs), obtained by culturing CD34+ cells in the presence of SCF and IL-6 (Saito et al., 1996; Kempuraj et al., 1999). hCBMCs are predominantly MCT (tryptase-positive and chymase-negative) rather than MCTC (tryptase- and chymase-double-positive) type (Toru et al., 1998; Ahn et al., 2000). hCBMCs produce several Mediators that include histamine, tryptase, LTs, PGD2, IL-1, IL-5, IL-6, IL-8, IL-13, SCF, TNF-α, granulocyte–macrophage colony-stimulating factor (GM-CSF) (Yanagida et al., 1995; Ahn et al., 2000; Kimata et al., 2000b; Tachimoto et al., 2000), as well as corticotropin-releasing hormone and its structurally related urocortin (Kempuraj et al., 2004). Flavonoids is a group of naturally occurring polyphenolic compounds found in fruits, vegetables, nuts, seeds, herbs, spices and red wine with antioxidant properties (Schroeter et al., 2003; Huxley et al., 2004; Lako et al., 2004). Flavonoids possess antiallergic, anti-inflammatory, cytoprotective and anticarcinogenic activity (Herrmann, 1976; Duthie et al., 1997; Middleton Jr et al., 2000; Theoharides et al., 2001). Several flavonoids with a hydroxylation pattern on the B phenolic ring, called flavonols, have been reported to inhibit histamine Release from murine mast cells (Foreman, 1984; Middleton Jr, 1998) and basophils (Middleton Jr & Drzewiecki, 1985), as well as IL-6 and TNF-α Release from bone marrow-derived cultured murine mast cells and rat peritoneal mast cells (Kimata et al., 2000b). Flavonoids are also known to affect many enzyme systems such as tyrosine and serine–threonine protein kinases, phospholipase A2, phospholipase C and lipoxygenase, all involved in allergic and inflammatory responses (Middleton Jr & Kandaswami, 1992). Certain flavonoids, such as quercetin, flavone and luteolin, can inhibit histamine, LTs, PGD2 and GM-CSF Release from cultured human mast cells (Kimata et al., 2000b; Theoharides et al., 2001), as well as IL-4 and IL-13 from activated basophils (Hirano et al., 2004). Crosslinking of the high-affinity receptors for IgE (FcɛRI) induces the activation of protein kinase C (PKC) and the elevation of intracellular Ca2+ concentration, believed to be the primary synergistic signals required for secretion. Mast cells also express the calcium-insensitive PKC isozyme theta (PKC θ), which is functional in FcɛRI-mediated activation (Liu et al., 2001). Here, we compared for the first time the effect of certain flavonols on the secretion of granule-stored and newly synthesized Mediators, along with their effect on two different targets, intracellular calcium ions and the calcium-insensitive PKC θ in hCBMCs. We showed that quercetin and kaempferol, more than myricetin and morin, inhibited secretion of proinflammatory cytokines; morin was the only flavonol that was a weak inhibitor of tryptase and histamine Release as well as of intracellular calcium levels. All flavonols inhibited activation of PKC θ.

Duraisamy Kempuraj - One of the best experts on this subject based on the ideXlab platform.

  • mercury induces inflammatory Mediator Release from human mast cells
    Journal of Neuroinflammation, 2010
    Co-Authors: Duraisamy Kempuraj, Shahrzad Asadi, Bodi Zhang, Akrivi Manola, Jennifer Hogan, Erika Peterson, Theoharis C Theoharides
    Abstract:

    Background: Mercury is known to be neurotoxic, but its effects on the immune system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD) have “allergic” symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl2) on human mast cell activation. Methods: Human leukemic cultured LAD2 mast cells and normal human umbilical cord blood-derived cultured mast cells (hCBMCs) were stimulated by HgCl2 (0.1-10 μM) for either 10 min for beta-hexosaminidase Release or 24 hr for measuring vascular endothelial growth factor (VEGF) and IL-6 Release by ELISA. Results: HgCl2 induced a 2-fold increase in b-hexosaminidase Release, and also significant VEGF Release at 0.1 and 1 μM (311 ± 32 pg/10 6 cells and 443 ± 143 pg/10 6 cells, respectively) from LAD2 mast cells compared to control cells (227 ± 17 pg/10 6 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 μM) to the proinflammatory neuropeptide substance P (SP, 0.1 μM) had synergestic action in inducing VEGF from LAD2 mast cells. HgCl2 also stimulated significant VEGF Release (360 ± 100 pg/10 6 cells at 1 μM, n = 5, p < 0.05) from hCBMCs compared to control cells (182 ± 57 pg/10 6 cells), and IL-6 Release (466 ± 57 pg/10 6 cells at 0.1 μM) compared to untreated cells (13 ± 25 pg/10 6 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 μM) to SP (5 μM) further increased IL-6 Release. Conclusions: HgCl2 stimulates VEGF and IL-6 Release from human mast cells. This phenomenon could disrupt the blood-brain-barrier and permit brain inflammation. As a result, the findings of the present study provide a biological mechanism for how low levels of mercury may contribute to ASD pathogenesis.

  • flavonols inhibit proinflammatory Mediator Release intracellular calcium ion levels and protein kinase c theta phosphorylation in human mast cells
    British Journal of Pharmacology, 2005
    Co-Authors: Duraisamy Kempuraj, B Madhappan, Spyridon Christodoulou, William Boucher, Jing Cao, Nikoletta Papadopoulou, Curtis L Cetrulo, Theoharis C Theoharides
    Abstract:

    Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which -- the flavonols, inhibits histamine and some cytokine Release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory Mediator Release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 microM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-alpha was inhibited by 82-93% at 100 microM quercetin and kaempferol, and 31-70% by myricetin and morin. Tryptase Release was inhibited by 79-96% at 100 microM quercetin, kampferol and myricetin, but only 39% by morin; histamine Release was inhibited 52-77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose-response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC theta). Flavonol inhibition of IgE-mediated proinflammatory Mediator Release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC theta signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases.

  • flavonols inhibit proinflammatory Mediator Release intracellular calcium ion levels and protein kinase c theta phosphorylation in human mast cells
    British Journal of Pharmacology, 2005
    Co-Authors: Duraisamy Kempuraj, B Madhappan, Spyridon Christodoulou, William Boucher, Nikoletta Papadopoulou, Curtis L Cetrulo, Theoharis C Theoharides
    Abstract:

    Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which – the flavonols, inhibits histamine and some cytokine Release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory Mediator Release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 μM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-α was inhibited by 82–93% at 100 μM quercetin and kaempferol, and 31–70% by myricetin and morin. Tryptase Release was inhibited by 79–96% at 100 μM quercetin, kampferol and myricetin, but only 39% by morin; histamine Release was inhibited 52–77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose–response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC θ). Flavonol inhibition of IgE-mediated proinflammatory Mediator Release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC θ signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases. Keywords: Cytokines, flavonols, mast cells, PKC θ, tryptase, quercetin Introduction Mast cells are important effector cells in IgE-mediated reactions by secreting histamine, chymase, tryptase, leukotrienes (LTs), prostaglandin D2 (PGD2) and several multifunctional cytokines; they include interleukin-6 (IL-6), IL-8, IL-13, tumor necrosis factor-alpha (TNF-α), stem cell factor (SCF) and many chemotactic factors (Galli, 2000; Mekori & Metcalfe, 2000). These cytokines contribute to the late-phase allergic reactions and to allergic inflammation through the recruitment of immune cells into the site of inflammation (Wedemeyer et al., 2000; Theoharides & Cochrane, 2004). Tryptase, expressed by all subsets of human mast cells and comprising up to 25% of the total intracellular proteins, has emerged as an important Mediator in allergic diseases (Shaoheng et al., 1998). Tryptase and other serine proteases are signaling molecules that cleave protease-activated surface receptor-2 (PAR-2) leading to widespread inflammation (Steinhoff et al., 2000; Cottrell et al., 2003). Calcium influx is necessary for mast cell Mediator secretion (Kimata et al., 2000b) and PAR-2 activation has also been associated with a brisk increase in intracellular calcium concentration (Dery et al., 1998). The limited number of mast cells obtained from normal human tissues has led to increasing use of human umbilical cord blood-derived cultured mast cells (hCBMCs), obtained by culturing CD34+ cells in the presence of SCF and IL-6 (Saito et al., 1996; Kempuraj et al., 1999). hCBMCs are predominantly MCT (tryptase-positive and chymase-negative) rather than MCTC (tryptase- and chymase-double-positive) type (Toru et al., 1998; Ahn et al., 2000). hCBMCs produce several Mediators that include histamine, tryptase, LTs, PGD2, IL-1, IL-5, IL-6, IL-8, IL-13, SCF, TNF-α, granulocyte–macrophage colony-stimulating factor (GM-CSF) (Yanagida et al., 1995; Ahn et al., 2000; Kimata et al., 2000b; Tachimoto et al., 2000), as well as corticotropin-releasing hormone and its structurally related urocortin (Kempuraj et al., 2004). Flavonoids is a group of naturally occurring polyphenolic compounds found in fruits, vegetables, nuts, seeds, herbs, spices and red wine with antioxidant properties (Schroeter et al., 2003; Huxley et al., 2004; Lako et al., 2004). Flavonoids possess antiallergic, anti-inflammatory, cytoprotective and anticarcinogenic activity (Herrmann, 1976; Duthie et al., 1997; Middleton Jr et al., 2000; Theoharides et al., 2001). Several flavonoids with a hydroxylation pattern on the B phenolic ring, called flavonols, have been reported to inhibit histamine Release from murine mast cells (Foreman, 1984; Middleton Jr, 1998) and basophils (Middleton Jr & Drzewiecki, 1985), as well as IL-6 and TNF-α Release from bone marrow-derived cultured murine mast cells and rat peritoneal mast cells (Kimata et al., 2000b). Flavonoids are also known to affect many enzyme systems such as tyrosine and serine–threonine protein kinases, phospholipase A2, phospholipase C and lipoxygenase, all involved in allergic and inflammatory responses (Middleton Jr & Kandaswami, 1992). Certain flavonoids, such as quercetin, flavone and luteolin, can inhibit histamine, LTs, PGD2 and GM-CSF Release from cultured human mast cells (Kimata et al., 2000b; Theoharides et al., 2001), as well as IL-4 and IL-13 from activated basophils (Hirano et al., 2004). Crosslinking of the high-affinity receptors for IgE (FcɛRI) induces the activation of protein kinase C (PKC) and the elevation of intracellular Ca2+ concentration, believed to be the primary synergistic signals required for secretion. Mast cells also express the calcium-insensitive PKC isozyme theta (PKC θ), which is functional in FcɛRI-mediated activation (Liu et al., 2001). Here, we compared for the first time the effect of certain flavonols on the secretion of granule-stored and newly synthesized Mediators, along with their effect on two different targets, intracellular calcium ions and the calcium-insensitive PKC θ in hCBMCs. We showed that quercetin and kaempferol, more than myricetin and morin, inhibited secretion of proinflammatory cytokines; morin was the only flavonol that was a weak inhibitor of tryptase and histamine Release as well as of intracellular calcium levels. All flavonols inhibited activation of PKC θ.

Bruce S Bochner - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of fceri dependent Mediator Release and calcium flux from human mast cells by sialic acid binding immunoglobulin like lectin 8 engagement
    The Journal of Allergy and Clinical Immunology, 2008
    Co-Authors: Hidenori Yokoi, Walter C. Hubbard, Oksoon Hong Choi, Brendan J Canning, Stephan Von Gunten, Carol A Bickel, Sherry A Hudson, Donald W Macglashan, Bruce S Bochner
    Abstract:

    BACKGROUND: Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of glycan-binding inhibitory receptors, and among them, Siglec-8 is selectively expressed on human eosinophils, basophils, and mast cells. On eosinophils, Siglec-8 engagement induces apoptosis, but its function on mast cells is unknown. OBJECTIVE: We sought to study the effect of Siglec-8 engagement on human mast cell survival and Mediator Release responses. METHODS: Human mast cells were generated from CD34+ precursors. Apoptosis was studied by using flow cytometry. Mast cell Mediator Release or human lung airway smooth muscle contraction was initiated by FcepsilonRI cross-linking with or without preincubation with Siglec-8 or control antibodies, and Release of Mediators was analyzed along with Ca++ flux. RBL-2H3 cells transfected with normal and mutated forms of Siglec-8 were used to study how Siglec-8 engagement alters Mediator Release. RESULTS: Siglec-8 engagement failed to induce human mast cell apoptosis. However, preincubation with Siglec-8 mAbs significantly (P < .05) inhibited FcepsilonRI-dependent histamine and prostaglandin D(2) Release, Ca++ flux, and anti-IgE-evoked contractions of human bronchial rings. In contrast, Release of IL-8 was not inhibited. Siglec-8 ligation was also shown to inhibit beta-hexosaminidase Release and Ca++ flux triggered through FcepsilonRI in RBL-2H3 cells transfected with full-length human Siglec-8 but not in cells transfected with Siglec-8 containing a tyrosine to phenylalanine point mutation in the membrane-proximal immunoreceptor tyrosine-based inhibitory motif domain. CONCLUSION: These data represent the first reported inhibitory effects of Siglec engagement on human mast cells.

  • The role of basophils in asthma.
    Annals of the New York Academy of Sciences, 1991
    Co-Authors: Lawrence M Lichtenstein, Bruce S Bochner
    Abstract:

    The characteristics of the acute and late human response to antigen in the upper and lower airways and in the skin is summarized in TABLE 2. This table makes it clear that while mast cells are responsible for the Mediator Release of the acute phase, eosinophils and basophils are the cells involved in the Mediator Release which occurs during the experimental late phase reaction. The pattern of Mediators observed during the acute response is quite characteristic of the mast cell. Thus, in the nose, skin, and lungs, the acute response is characterized by significant increases in histamine, PGD2, tryptase, and sometimes LTC4. In the late phase reaction, the pattern of Mediator Release is characteristic of basophils and eosinophils, and includes histamine, LTC4 (where measurable), and eosinophil-derived proteins, without PGD2 or tryptase. Basophils have been identified at appropriate time-points in each model using morphologic and phenotypic criteria, and their numbers relate to the histamine levels. Finally, treatment with glucocorticosteroids, the most potent drugs available for treating chronic allergic inflammation, obliterates the late phase reaction and decreases both Mediator Release and the infiltration of eosinophils and basophils. Chronic allergic inflammation is now taken by both the pulmonary and immunologic community as a hallmark of asthma, and it can be stated without equivocation that the basophils are responsible for the Mediator Release observed in that response.

Nikoletta Papadopoulou - One of the best experts on this subject based on the ideXlab platform.

  • flavonols inhibit proinflammatory Mediator Release intracellular calcium ion levels and protein kinase c theta phosphorylation in human mast cells
    British Journal of Pharmacology, 2005
    Co-Authors: Duraisamy Kempuraj, B Madhappan, Spyridon Christodoulou, William Boucher, Jing Cao, Nikoletta Papadopoulou, Curtis L Cetrulo, Theoharis C Theoharides
    Abstract:

    Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which -- the flavonols, inhibits histamine and some cytokine Release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory Mediator Release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 microM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-alpha was inhibited by 82-93% at 100 microM quercetin and kaempferol, and 31-70% by myricetin and morin. Tryptase Release was inhibited by 79-96% at 100 microM quercetin, kampferol and myricetin, but only 39% by morin; histamine Release was inhibited 52-77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose-response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC theta). Flavonol inhibition of IgE-mediated proinflammatory Mediator Release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC theta signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases.

  • flavonols inhibit proinflammatory Mediator Release intracellular calcium ion levels and protein kinase c theta phosphorylation in human mast cells
    British Journal of Pharmacology, 2005
    Co-Authors: Duraisamy Kempuraj, B Madhappan, Spyridon Christodoulou, William Boucher, Nikoletta Papadopoulou, Curtis L Cetrulo, Theoharis C Theoharides
    Abstract:

    Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which – the flavonols, inhibits histamine and some cytokine Release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory Mediator Release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 μM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-α was inhibited by 82–93% at 100 μM quercetin and kaempferol, and 31–70% by myricetin and morin. Tryptase Release was inhibited by 79–96% at 100 μM quercetin, kampferol and myricetin, but only 39% by morin; histamine Release was inhibited 52–77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose–response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC θ). Flavonol inhibition of IgE-mediated proinflammatory Mediator Release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC θ signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases. Keywords: Cytokines, flavonols, mast cells, PKC θ, tryptase, quercetin Introduction Mast cells are important effector cells in IgE-mediated reactions by secreting histamine, chymase, tryptase, leukotrienes (LTs), prostaglandin D2 (PGD2) and several multifunctional cytokines; they include interleukin-6 (IL-6), IL-8, IL-13, tumor necrosis factor-alpha (TNF-α), stem cell factor (SCF) and many chemotactic factors (Galli, 2000; Mekori & Metcalfe, 2000). These cytokines contribute to the late-phase allergic reactions and to allergic inflammation through the recruitment of immune cells into the site of inflammation (Wedemeyer et al., 2000; Theoharides & Cochrane, 2004). Tryptase, expressed by all subsets of human mast cells and comprising up to 25% of the total intracellular proteins, has emerged as an important Mediator in allergic diseases (Shaoheng et al., 1998). Tryptase and other serine proteases are signaling molecules that cleave protease-activated surface receptor-2 (PAR-2) leading to widespread inflammation (Steinhoff et al., 2000; Cottrell et al., 2003). Calcium influx is necessary for mast cell Mediator secretion (Kimata et al., 2000b) and PAR-2 activation has also been associated with a brisk increase in intracellular calcium concentration (Dery et al., 1998). The limited number of mast cells obtained from normal human tissues has led to increasing use of human umbilical cord blood-derived cultured mast cells (hCBMCs), obtained by culturing CD34+ cells in the presence of SCF and IL-6 (Saito et al., 1996; Kempuraj et al., 1999). hCBMCs are predominantly MCT (tryptase-positive and chymase-negative) rather than MCTC (tryptase- and chymase-double-positive) type (Toru et al., 1998; Ahn et al., 2000). hCBMCs produce several Mediators that include histamine, tryptase, LTs, PGD2, IL-1, IL-5, IL-6, IL-8, IL-13, SCF, TNF-α, granulocyte–macrophage colony-stimulating factor (GM-CSF) (Yanagida et al., 1995; Ahn et al., 2000; Kimata et al., 2000b; Tachimoto et al., 2000), as well as corticotropin-releasing hormone and its structurally related urocortin (Kempuraj et al., 2004). Flavonoids is a group of naturally occurring polyphenolic compounds found in fruits, vegetables, nuts, seeds, herbs, spices and red wine with antioxidant properties (Schroeter et al., 2003; Huxley et al., 2004; Lako et al., 2004). Flavonoids possess antiallergic, anti-inflammatory, cytoprotective and anticarcinogenic activity (Herrmann, 1976; Duthie et al., 1997; Middleton Jr et al., 2000; Theoharides et al., 2001). Several flavonoids with a hydroxylation pattern on the B phenolic ring, called flavonols, have been reported to inhibit histamine Release from murine mast cells (Foreman, 1984; Middleton Jr, 1998) and basophils (Middleton Jr & Drzewiecki, 1985), as well as IL-6 and TNF-α Release from bone marrow-derived cultured murine mast cells and rat peritoneal mast cells (Kimata et al., 2000b). Flavonoids are also known to affect many enzyme systems such as tyrosine and serine–threonine protein kinases, phospholipase A2, phospholipase C and lipoxygenase, all involved in allergic and inflammatory responses (Middleton Jr & Kandaswami, 1992). Certain flavonoids, such as quercetin, flavone and luteolin, can inhibit histamine, LTs, PGD2 and GM-CSF Release from cultured human mast cells (Kimata et al., 2000b; Theoharides et al., 2001), as well as IL-4 and IL-13 from activated basophils (Hirano et al., 2004). Crosslinking of the high-affinity receptors for IgE (FcɛRI) induces the activation of protein kinase C (PKC) and the elevation of intracellular Ca2+ concentration, believed to be the primary synergistic signals required for secretion. Mast cells also express the calcium-insensitive PKC isozyme theta (PKC θ), which is functional in FcɛRI-mediated activation (Liu et al., 2001). Here, we compared for the first time the effect of certain flavonols on the secretion of granule-stored and newly synthesized Mediators, along with their effect on two different targets, intracellular calcium ions and the calcium-insensitive PKC θ in hCBMCs. We showed that quercetin and kaempferol, more than myricetin and morin, inhibited secretion of proinflammatory cytokines; morin was the only flavonol that was a weak inhibitor of tryptase and histamine Release as well as of intracellular calcium levels. All flavonols inhibited activation of PKC θ.

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  • flavonols inhibit proinflammatory Mediator Release intracellular calcium ion levels and protein kinase c theta phosphorylation in human mast cells
    British Journal of Pharmacology, 2005
    Co-Authors: Duraisamy Kempuraj, B Madhappan, Spyridon Christodoulou, William Boucher, Jing Cao, Nikoletta Papadopoulou, Curtis L Cetrulo, Theoharis C Theoharides
    Abstract:

    Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which -- the flavonols, inhibits histamine and some cytokine Release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory Mediator Release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 microM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-alpha was inhibited by 82-93% at 100 microM quercetin and kaempferol, and 31-70% by myricetin and morin. Tryptase Release was inhibited by 79-96% at 100 microM quercetin, kampferol and myricetin, but only 39% by morin; histamine Release was inhibited 52-77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose-response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC theta). Flavonol inhibition of IgE-mediated proinflammatory Mediator Release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC theta signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases.

  • flavonols inhibit proinflammatory Mediator Release intracellular calcium ion levels and protein kinase c theta phosphorylation in human mast cells
    British Journal of Pharmacology, 2005
    Co-Authors: Duraisamy Kempuraj, B Madhappan, Spyridon Christodoulou, William Boucher, Nikoletta Papadopoulou, Curtis L Cetrulo, Theoharis C Theoharides
    Abstract:

    Mast cells participate in allergies, and also in immunity and inflammation by secreting proinflammatory cytokines. Flavonoids are naturally occurring polyphenolic plant compounds, one group of which – the flavonols, inhibits histamine and some cytokine Release from rodent basophils and mast cells. However, the effect of flavonols on proinflammatory Mediator Release and their possible mechanism of action in human mast cells is not well defined. Human umbilical cord blood-derived cultured mast cells (hCBMCs) grown in the presence of stem cell factor (SCF) and interleukin (IL)-6 were preincubated for 15 min with the flavonols quercetin, kaempferol, myricetin and morin (0.01, 0.1, 1, 10 or 100 μM), followed by activation with anti-IgE. Secretion was quantitated for IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), histamine and tryptase levels. Release of IL-6, IL-8 and TNF-α was inhibited by 82–93% at 100 μM quercetin and kaempferol, and 31–70% by myricetin and morin. Tryptase Release was inhibited by 79–96% at 100 μM quercetin, kampferol and myricetin, but only 39% by morin; histamine Release was inhibited 52–77% by the first three flavonols, but only 28% by morin. These flavonols suppressed intracellular calcium ion elevations in a dose–response manner, with morin being the weakest; they also inhibited phosphorylation of the calcium-insensitive protein kinase C theta (PKC θ). Flavonol inhibition of IgE-mediated proinflammatory Mediator Release from hCBMCs may be due to inhibition of intracellular calcium influx and PKC θ signaling. Flavonols may therefore be suitable for the treatment of allergic and inflammatory diseases. Keywords: Cytokines, flavonols, mast cells, PKC θ, tryptase, quercetin Introduction Mast cells are important effector cells in IgE-mediated reactions by secreting histamine, chymase, tryptase, leukotrienes (LTs), prostaglandin D2 (PGD2) and several multifunctional cytokines; they include interleukin-6 (IL-6), IL-8, IL-13, tumor necrosis factor-alpha (TNF-α), stem cell factor (SCF) and many chemotactic factors (Galli, 2000; Mekori & Metcalfe, 2000). These cytokines contribute to the late-phase allergic reactions and to allergic inflammation through the recruitment of immune cells into the site of inflammation (Wedemeyer et al., 2000; Theoharides & Cochrane, 2004). Tryptase, expressed by all subsets of human mast cells and comprising up to 25% of the total intracellular proteins, has emerged as an important Mediator in allergic diseases (Shaoheng et al., 1998). Tryptase and other serine proteases are signaling molecules that cleave protease-activated surface receptor-2 (PAR-2) leading to widespread inflammation (Steinhoff et al., 2000; Cottrell et al., 2003). Calcium influx is necessary for mast cell Mediator secretion (Kimata et al., 2000b) and PAR-2 activation has also been associated with a brisk increase in intracellular calcium concentration (Dery et al., 1998). The limited number of mast cells obtained from normal human tissues has led to increasing use of human umbilical cord blood-derived cultured mast cells (hCBMCs), obtained by culturing CD34+ cells in the presence of SCF and IL-6 (Saito et al., 1996; Kempuraj et al., 1999). hCBMCs are predominantly MCT (tryptase-positive and chymase-negative) rather than MCTC (tryptase- and chymase-double-positive) type (Toru et al., 1998; Ahn et al., 2000). hCBMCs produce several Mediators that include histamine, tryptase, LTs, PGD2, IL-1, IL-5, IL-6, IL-8, IL-13, SCF, TNF-α, granulocyte–macrophage colony-stimulating factor (GM-CSF) (Yanagida et al., 1995; Ahn et al., 2000; Kimata et al., 2000b; Tachimoto et al., 2000), as well as corticotropin-releasing hormone and its structurally related urocortin (Kempuraj et al., 2004). Flavonoids is a group of naturally occurring polyphenolic compounds found in fruits, vegetables, nuts, seeds, herbs, spices and red wine with antioxidant properties (Schroeter et al., 2003; Huxley et al., 2004; Lako et al., 2004). Flavonoids possess antiallergic, anti-inflammatory, cytoprotective and anticarcinogenic activity (Herrmann, 1976; Duthie et al., 1997; Middleton Jr et al., 2000; Theoharides et al., 2001). Several flavonoids with a hydroxylation pattern on the B phenolic ring, called flavonols, have been reported to inhibit histamine Release from murine mast cells (Foreman, 1984; Middleton Jr, 1998) and basophils (Middleton Jr & Drzewiecki, 1985), as well as IL-6 and TNF-α Release from bone marrow-derived cultured murine mast cells and rat peritoneal mast cells (Kimata et al., 2000b). Flavonoids are also known to affect many enzyme systems such as tyrosine and serine–threonine protein kinases, phospholipase A2, phospholipase C and lipoxygenase, all involved in allergic and inflammatory responses (Middleton Jr & Kandaswami, 1992). Certain flavonoids, such as quercetin, flavone and luteolin, can inhibit histamine, LTs, PGD2 and GM-CSF Release from cultured human mast cells (Kimata et al., 2000b; Theoharides et al., 2001), as well as IL-4 and IL-13 from activated basophils (Hirano et al., 2004). Crosslinking of the high-affinity receptors for IgE (FcɛRI) induces the activation of protein kinase C (PKC) and the elevation of intracellular Ca2+ concentration, believed to be the primary synergistic signals required for secretion. Mast cells also express the calcium-insensitive PKC isozyme theta (PKC θ), which is functional in FcɛRI-mediated activation (Liu et al., 2001). Here, we compared for the first time the effect of certain flavonols on the secretion of granule-stored and newly synthesized Mediators, along with their effect on two different targets, intracellular calcium ions and the calcium-insensitive PKC θ in hCBMCs. We showed that quercetin and kaempferol, more than myricetin and morin, inhibited secretion of proinflammatory cytokines; morin was the only flavonol that was a weak inhibitor of tryptase and histamine Release as well as of intracellular calcium levels. All flavonols inhibited activation of PKC θ.