Marine brevetoxin induces IgE-independent mast cell activation.
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.
Hilderbrand
Susana C
SC
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, Greenville, NC 27834, USA.
Murrell
Rachel N
RN
Gibson
James E
JE
Brown
Jared M
JM
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
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