title: Marine brevetoxin induces IgE-independent mast cell activation.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, Greenville, NC 27834, USA.
authors.forename: Susana C
authors.initials: SC
authors.lastname: Hilderbrand
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Murrell
authors.forename: James E
authors.initials: JE
authors.lastname: Gibson
authors.forename: Jared M
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells; D020013:Calcium Signaling; D015550:Cell Degranulation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004987:Ethers / Q000494:pharmacology; D007073:Immunoglobulin E / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008387:Marine Toxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D035964:Oxocins; D011108:Polymers / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017455:Receptors, IgE / Q000819:agonists; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000037:antagonists & inhibitors / Q000633:toxicity
chemical_list: D004987:Ethers; D015850:Interleukin-6; D008387:Marine Toxins; D009498:Neurotoxins; D035964:Oxocins; D011108:Polymers; C051732:Ptychodiscus brevis T2 toxin; D012333:RNA, Messenger; D017455:Receptors, IgE; D026941:Sodium Channel Blockers; C489035:brevenal (polyether); D007073:Immunoglobulin E; D012964:Sodium