The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells Zuyi Weng, MS, PhD, Arti B. Patel, MS, Smaro Panagiotidou, MA, Theoharis.

Slides:

Advertisements

Similar presentations

Dorothea Dijkstra, MSc, Rob Leurs, PhD, Paul Chazot, PhD, Fiona C

Advertisements

Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2 Natalija Novak, MD, Nihal Mete, MD, Caroline.

Low-affinity allergen-specific IgE in cord blood and affinity maturation after birth Norio Kamemura, PhD, Norio Kawamoto, MD, PhD, Ryosuke Nakamura, PhD,

Mast cell activation by fibrinogen-related homologous c-terminal peptides (haptides) modulates systemic blood pressure Maamoun Basheer, MSc, Herzl Schwalb,

Activation of mast cells by double-stranded RNA: evidence for activation through Toll- like receptor 3 Marianna Kulka, PhD, Lena Alexopoulou, PhD, Richard.

Epoxyeicosatrienoic acids are involved in the C70 fullerene derivative–induced control of allergic asthma Sarah K. Norton, PhD, Dayanjan S. Wijesinghe,

Modulation of basophil activity: A novel function of the neuropeptide α-melanocyte– stimulating hormone Markus Böhm, MD, Mara Apel, Koji Sugawara, MD,

Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor Israa.

Mechanisms of vitamin D3 metabolite repression of IgE-dependent mast cell activation Kwok-Ho Yip, PhD, Natasha Kolesnikoff, PhD, Chunping Yu, BSc(Hons),

Liping Xie, MD, John T. Schroeder, PhD, Jacqueline M

Ibrutinib, a Bruton’s tyrosine kinase inhibitor used for treatment of lymphoproliferative disorders, eliminates both aeroallergen skin test and basophil.

The sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 axis regulates early airway T-cell infiltration in murine mast cell–dependent acute allergic.

Prostaglandin E2 suppresses CCL27 production through EP2 and EP3 receptors in human keratinocytes Naoko Kanda, MD, PhD, Hiroshi Mitsui, MD, PhD, Shinichi.

S100A12 provokes mast cell activation: A potential amplification pathway in asthma and innate immunity Zheng Yang, PhD, Wei Xing Yan, PhD, Hong Cai,

IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease

Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy Emilie Collmann, PhD, Thomas Bohnacker, PhD, Romina.

Ramipril and metoprolol intake aggravate human and murine anaphylaxis: Evidence for direct mast cell priming Maria Nassiri, MS, Magda Babina, PhD, Sabine.

Histamine H2 receptor stimulation upregulates TH2 chemokine CCL17 production in human M2a macrophages Susanne Mommert, PhD, Karl Gregor, MD, Kristine.

Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock Yuki Nakamura, PhD, Nobuhiro Nakano, PhD, Kayoko Ishimaru,

Epicutaneous sensitization results in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis Lisa M. Bartnikas, MD, Michael F. Gurish,

Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses Tina L. Sumpter, PhD, Chin H. Ho, MD, Anna.

Is 9 more than 2 also in allergic airway inflammation?

Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor Israa.

ERK1/2 antagonize AMPK-dependent regulation of FcεRI-mediated mast cell activation and anaphylaxis Seung-Lark Hwang, PhD, Yue Lu, PhD, Xian Li, MSc,

Specificity protein 1 is pivotal in the skin’s antiviral response

Sphingomyelin and ceramide are physiological ligands for human LMIR3/CD300f, inhibiting FcεRI-mediated mast cell activation Kumi Izawa, MD, PhD, Masamichi.

Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk Jun Ho Lee, PhD, Jie Wan Kim,

Pharmacologic inhibition of Notch signaling suppresses food antigen–induced mucosal mast cell hyperplasia Asuka Honjo, MD, Nobuhiro Nakano, PhD, Susumu.

A mouse Fcγ-Fcε protein that inhibits mast cells through activation of FcγRIIB, SH2 domain–containing inositol phosphatase 1, and SH2 domain–containing.

Lung mast cells are a source of secreted phospholipases A2

Circadian clock gene Period2 regulates a time-of-day–dependent variation in cutaneous anaphylactic reaction Yuki Nakamura, Daisuke Harama, Naomi Shimokawa,

Differential roles for the IL-9/IL-9 receptor α-chain pathway in systemic and oral antigen–induced anaphylaxis Heather Osterfeld, BSc, Richard Ahrens,

Toll-like receptor 9 suppression in plasmacytoid dendritic cells after IgE-dependent activation is mediated by autocrine TNF-α John T. Schroeder, PhD,

Molecular determinants of allergen-induced effector cell degranulation

Toluene downregulates filaggrin expression via the extracellular signal-regulated kinase and signal transducer and activator of transcription–dependent.

Beatrix Schäfer, PhD, Adrian M

A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally Elsa Mazuc, MSc, Bruno O. Villoutreix, PhD, Odile.

Toll-like receptor 3 enhances late-phase reaction of experimental allergic conjunctivitis Mayumi Ueta, MD, PhD, Satoshi Uematsu, MD, PhD, Shizuo Akira,

Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes Xiuju Dai, MD, PhD, Koji Sayama, MD, PhD, Mikiko Tohyama,

A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma

Culture medium from TNF-α–stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms Wenru Su, MD,

Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD,

Dexamethasone regulation of thymic stromal lymphopoietin receptor expression on mast cells and their precursors Zoulfia Allakhverdi, PhD, Michael R.

Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: Relevance to atopic dermatitis Bodi.

Inhibition of FcεRI-dependent mediator release and calcium flux from human mast cells by sialic acid–binding immunoglobulin-like lectin 8 engagement

Food allergy herbal formula 2 protection against peanut anaphylactic reaction is via inhibition of mast cells and basophils Ying Song, MD, Chunfeng Qu,

Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions Maria José Torres, MD, PhD,

Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice Hong Cui, MD,

Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide Weishan Huang, PhD, J. Luis Morales,

Role of hyaluronan and hyaluronan-binding proteins in human asthma

Airway epithelial cells activate TH2 cytokine production in mast cells through IL-1 and thymic stromal lymphopoietin Deepti R. Nagarkar, PhD, Julie A.

Nitric oxide inhibits IFN regulatory factor 1 and nuclear factor-κB pathways in rhinovirus- infected epithelial cells Rommy Koetzler, MD, MSc, Raza S.

High serum corticotropin-releasing hormone (CRH) and bone marrow mast cell CRH receptor expression in a mastocytosis patient Theoharis C. Theoharides,

3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6–type cytokine actions by targeting the glycoprotein 130 subunit: Potential clinical implications

DJ-1 regulates mast cell activation and IgE-mediated allergic responses Do Kyun Kim, PhD, Hyuk Soon Kim, MS, A-Ram Kim, MS, Ji Hyung Kim, BS, Bokyung.

Amplification of Toll-like receptor–mediated signaling through spleen tyrosine kinase in human B-cell activation Shigeru Iwata, MD, PhD, Kunihiro Yamaoka,

MicroRNA-4443 regulates mast cell activation by T cell–derived microvesicles Irit Shefler, PhD, Pazit Salamon, PhD, Francesca Levi-Schaffer, PharmD, Adam.

Activation of human mast cells through the platelet-activating factor receptor Naoki Kajiwara, PhD, Tomomi Sasaki, BSc, Peter Bradding, DM, Glenn Cruse,

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Low-affinity allergen-specific IgE in cord blood and affinity maturation after birth Norio Kamemura, PhD, Norio Kawamoto, MD, PhD, Ryosuke Nakamura, PhD,

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis Meiqin Wang, MD, PhD, Julita Ramirez, DVM, PhD,

Antigen coupled with Lewis-x trisaccharides elicits potent immune responses in mice Shih-Chang Hsu, BS, Tsung-Hsien Tsai, MD, Hirokazu Kawasaki, PhD,

Liping Xie, MD, John T. Schroeder, PhD, Jacqueline M

Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor Grzegorz Woszczek, MD, PhD, Li-Yuan Chen, PhD,

Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity James N. Francis, PhD, Louisa.

Dorothea Dijkstra, MSc, Rob Leurs, PhD, Paul Chazot, PhD, Fiona C

Nuclear factor (erythroid-derived 2)-like-2 pathway modulates substance P–induced human mast cell activation and degranulation in the hair follicle Laura.

Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma

The effects of gastric digestion on codfish allergenicity

Natural history of cow’s milk allergy

Presentation transcript:

The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells Zuyi Weng, MS, PhD, Arti B. Patel, MS, Smaro Panagiotidou, MA, Theoharis C. Theoharides, MS, PhD, MD Journal of Allergy and Clinical Immunology Volume 135, Issue 4, Pages 1044-1052.e5 (April 2015) DOI: 10.1016/j.jaci.2014.10.032 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Methlut inhibits degranulation of LAD2 cells stimulated by SP. MCs were preincubated with either cromolyn (Crom), luteolin (Lut), or methlut (10-100 μmol/L for 30 minutes) before stimulation with SP (2 μmol/L for 30 minutes). A, β-Hexosaminidase. B, Preformed TNF release. *P < .05 and **P < .01. ns, Not significant. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Dose response of the inhibitory effect of methlut on degranulation of LAD2 cells stimulated by SP. MCs were preincubated with either luteolin (Lut) or methlut (10-100 μmol/L for 30 minutes) before stimulation with SP (2 μmol/L for 30 minutes). A, β-Hexosaminidase. B, Histamine. C, Preformed TNF release. *P < .05. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Methlut inhibits degranulation of LAD2 cells stimulated by IgE/anti-IgE. After overnight priming with IgE (1 μg/mL), LAD2 cells were incubated with luteolin (Lut) or methlut (50 or 100 μmol/L for 30 minutes) before anti-IgE stimulation (10 μg/mL) for 2 hours. A, β-Hexosaminidase. B, Preformed TNF. **P < .001. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Methlut inhibits TNF mRNA expression in LAD2 cells stimulated by SP. LAD2 cells were incubated with luteolin (Lut; A) or methlut (B; 1-50 μmol/L up to 24 hours) before SP stimulation (2 μmol/L for 24 hours), and TNF release was assayed. In another set of experiments, LAD2 cells were incubated with luteolin (C) or methlut (D; 10 or 50 μmol/L for 30 minutes) before SP stimulation (2 μmol/L for 6 hours), and mRNA expression was examined. *P < .05. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Methlut inhibits CCL2 synthesis and release from hCBMCs stimulated by IgE/anti-IgE. After overnight priming with IgE (1 μg/mL), hCBMCs were incubated with luteolin (Lut) or methlut (10 or 50 μmol/L for 30 minutes) before anti-IgE stimulation (10 μg/mL). A, CCL2 release was assayed at 24 hours after stimulation. B, CCL2 mRNA expression. hCBMCs were incubated with luteolin or methlut (50 μmol/L for 30 minutes) before stimulation with anti-IgE (10 μg/mL for 6 hours), and mRNA expression of CCL2 was examined. *P < .05. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Methlut inhibits NF-κB activation. LAD2 cells were incubated with luteolin (Lut) or methlut (10 or 50 μmol/L for 6 hours) before SP stimulation (2 μmol/L for 15 minutes). A, IκBα phosphorylation was detected and presented as fold relative to control. B, NF-κB p65 DNA-binding activity in the nuclear fraction was examined and expressed as fold relative to control. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Methlut inhibits NF-κB mRNA expression. A and B, LAD2 cells were incubated with luteolin (Lut) or methlut (10-100 μmol/L for 30 minutes) before SP stimulation (2 μmol/L for 6 hours). C and D, hCBMCs were primed overnight with IgE (1 μg/mL) and then incubated with lut or methlut (50 μmol/L for 30 minutes) before anti-IgE stimulation (10 μg/mL for 6 hours). mRNA expression levels of NFKB1 and RELA were examined. *P < .05. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Methlut inhibits mouse skin Evans blue extravasation. Mice were passively sensitized to DBP-HSA and injected with Evans blue through the tail vain. MCs were pretreated with methlut (100 μmol/L) 10 minutes before intradermal challenge. Photographs of mouse skin showing extravasated Evans blue before (A) and after (B) pretreatment with methlut. NS, Normal saline. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Structures are shown for cromolyn (A), flavone backbone (B), luteolin (C), and methlut (D). Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Purity of methlut. Analysis was done by means of mass spectrometry, as detailed in the Methods section. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Cromolyn (Crom) loses its inhibitory effect on LAD2 cell degranulation if used as pretreatment. MCs were preincubated with cromolyn (100 μmol/L) for 30 minutes before stimulation with either SP (2 μmol/L) or anti-IgE (10 μg/mL) for an additional 30 minutes. A, β-Hexosaminidase release. B, Histamine release. ns, No statistical significance. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Methlut and luteolin (Lut) inhibit intracellular calcium level increase. LAD2 cells were loaded with Fura-2 AM (30 nmol/L for 20 minutes) and then preincubated with luteolin or methlut (10 and 50 μmol/L for 30 minutes). Immediately after stimulation with SP (2 μmol/L), Fura-2 AM fluorescence was monitored at an excitation wavelength of 340 nm and 380 nm and an emission wavelength of 510 nm. Control cells were treated with 0.1% DMSO. The curve shown is representative of 5 experiments with similar results. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Luteolin and methlut do not affect intracellular ATP levels. After incubation with luteolin (A) or methlut (B; 10-100 μmol/L up to 24 h), 1 × 106 LAD2 cells were lysed, and intracellular ATP contents were determined. Journal of Allergy and Clinical Immunology 2015 135, 1044-1052.e5DOI: (10.1016/j.jaci.2014.10.032) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions