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Marine brevetoxin induces IgE-independent mast cell activation

  • Molecular Toxicology
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Abstract

Brevetoxins (PbTx) are sodium channel neurotoxins produced by the marine dinoflagellate Karenia brevis during red tide blooms. Inhalation of PbTx in normal individuals and individuals with pre-existing airways disease results in adverse airway symptoms including bronchoconstriction. In animal models of allergic inflammation, inhalation of PbTx results in a histamine H1-mediated bronchoconstriction suggestive of mast cell activation. How mast cells would respond directly to PbTx is unknown. We thus explored the activation of mouse bone marrow–derived mast cells (BMMCs) following exposure to purified PbTx-2. Following in vitro exposure to PbTx-2, we examined cellular viability, mast cell degranulation (β-hexosaminidase release), intracellular Ca2+ and Na+ flux, and the production of inflammatory mediators (IL-6). PbTx-2 induced significant cellular toxicity within 24 h as measured by LDH release and Annexin-V staining. However, within 1 h of exposure, PbTx-2 induced BMMC degranulation and an increase in IL-6 mRNA expression independent of the high-affinity IgE receptor (FcεRI) stimulation. Activation of BMMCs by PbTx-2 was associated with altered intracellular Ca2+ and Na+ levels. Brevenal, a naturally produced compound that antagonizes the activity of PbTx, prevented changes in intracellular Na+ levels but did not alter activation of BMMCs by PbTx-2. These findings demonstrate that PbTx-2 activates mast cells independent of FcεRI providing insight into critical events in the pathogenesis and a potential therapeutic target in brevetoxin-induced airway symptoms.

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References

  • Abraham WM, Bourdelais AJ, Ahmed A, Serebriakov I, Baden DG (2005a) Effects of inhaled brevetoxins in allergic airways: toxin-allergen interactions and pharmacologic intervention. Environ Health Perspect 113:632–637

    Article  CAS  PubMed  Google Scholar 

  • Abraham WM, Bourdelais AJ, Sabater JR, Ahmed A, Lee TA, Serebriakov I, Baden DG (2005b) Airway responses to aerosolized brevetoxins in an animal model of asthma. Am J Respir Crit Care Med 171:26–34

    Article  PubMed  Google Scholar 

  • Amin K, Janson C, Boman G, Venge P (2005) The extracellular deposition of mast cell products is increased in hypertrophic airways smooth muscles in allergic asthma but not in nonallergic asthma. Allergy 60:1241–1247

    Article  CAS  PubMed  Google Scholar 

  • Backer LC, Fleming LE, Rowan A, Cheng YS, Benson J, Pierce RH, Zaias J, Bean J, Bossart GD, Johnson D, Quimbo R, Baden DG (2003) Recreational exposure to aerosolized brevetoxins during Florida red tide events. Harmful Algae 2:19–28

    Article  CAS  PubMed  Google Scholar 

  • Backer LC, Kirkpatrick B, Fleming LE, Cheng YS, Pierce R, Bean JA, Clark R, Johnson D, Wanner A, Tamer R, Zhou Y, Baden DG (2005) Occupational exposure to aerosolized brevetoxins during Florida red tide events: effects on a healthy worker population. Environ Health Perspect 113:644–649

    Article  CAS  PubMed  Google Scholar 

  • Begueret H, Berger P, Vernejoux JM, Dubuisson L, Marthan R, Tunon-de-Lara JM (2007) Inflammation of bronchial smooth muscle in allergic asthma. Thorax 62:8–15

    Article  CAS  PubMed  Google Scholar 

  • Berger P, Compton SJ, Molimard M, Walls AF, N’Guyen C, Marthan R, Tunon-De-Lara JM (1999) Mast cell tryptase as a mediator of hyper responsiveness in human isolated bronchi. Clin Exp Allergy 29:804–812

    Article  CAS  PubMed  Google Scholar 

  • Berger P, N’Guyen C, Buckley M, Scotto-Gomez E, Marthan R, Tunon-de-Lara JM (2002) Passive sensitization of human airways induces mast cell degranulation and release of tryptase. Allergy 57:592–599

    Article  CAS  PubMed  Google Scholar 

  • Bottein Dechraoui MY, Ramsdell JS (2003) Type B brevetoxins show tissue selectivity for voltage-gated sodium channels: comparison of brain, skeletal muscle and cardiac sodium channels. Toxicon 41:919–927

    Article  CAS  PubMed  Google Scholar 

  • Bourdelais AJ, Campbell S, Jacocks H, Naar J, Wright JL, Carsi J, Baden DG (2004) Brevenal is a natural inhibitor of brevetoxin action in sodium channel receptor binding assays. Cell Mol Neurobiol 24:553–563

    Article  CAS  PubMed  Google Scholar 

  • Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, Heusser CH, Howarth PH, Holgate ST (1994) Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 10:471–480

    CAS  PubMed  Google Scholar 

  • Bradding P, Okayama Y, Kambe N, Saito H (2003) Ion channel gene expression in human lung, skin, and cord blood-derived mast cells. J Leukoc Biol 73:614–620

    Article  CAS  PubMed  Google Scholar 

  • Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID (2002) Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 346:1699–1705

    Article  PubMed  Google Scholar 

  • Brown JM, Wilson TM, Metcalfe DD (2008) The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin Exp Allergy 38:4–18

    CAS  PubMed  Google Scholar 

  • Cheng YS, Zhou Y, Irvin CM, Pierce RH, Naar J, Backer LC, Fleming LE, Kirkpatrick B, Baden DG (2005) Characterization of marine aerosol for assessment of human exposure to brevetoxins. Environ Health Perspect 113:638–643

    Article  CAS  PubMed  Google Scholar 

  • Di Capite J, Parekh AB (2009) CRAC channels and Ca2 + signaling in mast cells. Immunol Rev 231:45–58

    Article  CAS  PubMed  Google Scholar 

  • Fleming LE, Kirkpatrick B, Backer LC, Bean JA, Wanner A, Dalpra D, Tamer R, Zaias J, Cheng YS, Pierce R, Naar J, Abraham W, Clark R, Zhou Y, Henry MS, Johnson D, Van De Bogart G, Bossart GD, Harrington M, Baden DG (2005) Initial evaluation of the effects of aerosolized Florida red tide toxins (brevetoxins) in persons with asthma. Environ Health Perspect 113:650–657

    Article  CAS  PubMed  Google Scholar 

  • Fleming LE, Kirkpatrick B, Backer LC, Bean JA, Wanner A, Reich A, Zaias J, Cheng YS, Pierce R, Naar J, Abraham WM, Baden DG (2007) Aerosolized red-tide toxins (brevetoxins) and asthma. Chest 131:187–194

    Article  CAS  PubMed  Google Scholar 

  • Fleming LE, Bean JA, Kirkpatrick B, Cheng YS, Pierce R, Naar J, Nierenberg K, Backer LC, Wanner A, Reich A, Zhou Y, Watkins S, Henry M, Zaias J, Abraham WM, Benson J, Cassedy A, Hollenbeck J, Kirkpatrick G, Clarke T, Baden DG (2009) Exposure and effect assessment of aerosolized red tide toxins (brevetoxins) and asthma. Environ Health Perspect 117:1095–1100

    CAS  PubMed  Google Scholar 

  • Galli SJ, Tsai M, Piliponsky AM (2008) The development of allergic inflammation. Nature 454:445–454

    Article  CAS  PubMed  Google Scholar 

  • Hamid Q, Tulic M (2009) Immunobiology of asthma. Annu Rev Physiol 71:489–507

    Article  CAS  PubMed  Google Scholar 

  • Jensen BM, Swindle EJ, Iwaki S, Gilfillan AM (2006) Generation, isolation, and maintenance of rodent mast cells and mast cell lines. Curr Protoc Immunol 3(3):23

    PubMed  Google Scholar 

  • Kulagina NV, O’Shaughnessy TJ, Ma W, Ramsdell JS, Pancrazio JJ (2004) Pharmacological effects of the marine toxins, brevetoxin and saxitoxin, on murine frontal cortex neuronal networks. Toxicon 44:669–676

    Article  CAS  PubMed  Google Scholar 

  • Lombet A, Bidard JN, Lazdunski M (1987) Ciguatoxin and brevetoxins share a common receptor site on the neuronal voltage-dependent Na + channel. FEBS Lett 219:355–359

    Article  CAS  PubMed  Google Scholar 

  • Milian A, Nierenberg K, Fleming LE, Bean JA, Wanner A, Reich A, Backer LC, Jayroe D, Kirkpatrick B (2007) Reported respiratory symptom intensity in asthmatics during exposure to aerosolized Florida red tide toxins. J Asthma 44:583–587

    Article  CAS  PubMed  Google Scholar 

  • Murrell RN, Gibson JE (2009) Brevetoxins 2, 3, 6, and 9 show variability in potency and cause significant induction of DNA damage and apoptosis in Jurkat E6–1 cells. Arch Toxicol 83:1009–1019

    Article  CAS  PubMed  Google Scholar 

  • Pesci A, Foresi A, Bertorelli G, Chetta A, Olivieri D (1993) Histochemical characteristics and degranulation of mast cells in epithelium and lamina propria of bronchial biopsies from asthmatic and normal subjects. Am Rev Respir Dis 147:684–689

    CAS  PubMed  Google Scholar 

  • Purkerson SL, Baden DG, Fieber LA (1999) Brevetoxin modulates neuronal sodium channels in two cell lines derived from rat brain. Neurotoxicology 20:909–920

    CAS  PubMed  Google Scholar 

  • Purkerson-Parker SL, Fieber LA, Rein KS, Podona T, Baden DG (2000) Brevetoxin derivatives that inhibit toxin activity. Chem Biol 7:385–393

    Article  CAS  PubMed  Google Scholar 

  • Sayer A, Hu Q, Bourdelais AJ, Baden DG, Gibson JE (2005) The effect of brevenal on brevetoxin-induced DNA damage in human lymphocytes. Arch Toxicol 79:683–688

    Article  CAS  PubMed  Google Scholar 

  • Sekizawa K, Caughey GH, Lazarus SC, Gold WM, Nadel JA (1989) Mast cell tryptase causes airway smooth muscle hyper responsiveness in dogs. J Clin Invest 83:175–179

    Article  CAS  PubMed  Google Scholar 

  • Trainer VL, Baden DG, Catterall WA (1995) Detection of marine toxins using reconstituted sodium channels. J AOAC Int 78:570–573

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded by East Carolina University.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, Greenville, NC, 27834, USA

    Susana C. Hilderbrand, Rachel N. Murrell, James E. Gibson & Jared M. Brown

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  1. Susana C. Hilderbrand
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  2. Rachel N. Murrell
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  3. James E. Gibson
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  4. Jared M. Brown
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Correspondence to Jared M. Brown.

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Hilderbrand, S.C., Murrell, R.N., Gibson, J.E. et al. Marine brevetoxin induces IgE-independent mast cell activation. Arch Toxicol 85, 135–141 (2011). https://doi.org/10.1007/s00204-010-0564-2

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  • DOI: https://doi.org/10.1007/s00204-010-0564-2

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