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

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Presentation on theme: "The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells  Zuyi Weng, MS, PhD, Arti B. Patel, MS, Smaro Panagiotidou, MA, Theoharis."— Presentation transcript:

1 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 e5 (April 2015) DOI: /j.jaci Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Methlut inhibits degranulation of LAD2 cells stimulated by SP. MCs were preincubated with either cromolyn (Crom), luteolin (Lut), or methlut ( 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 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 ( 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 Methlut inhibits NF-κB mRNA expression. A and B, LAD2 cells were incubated with luteolin (Lut) or methlut ( 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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

11 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 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  , e5DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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

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