title: Knockout of the Trpc1 gene reveals that TRPC1 can promote recovery from anaphylaxis by negatively regulating mast cell TNF-α production.
abstract: Antigen-mediated mast cell (MC) degranulation is the critical early event in the induction of allergic reactions. Transient receptor potential channels (TRPC), particularly TRPC1, are thought to contribute to such MC activation. To explore the contribution of TRPC1 in MC-driven allergic reactions, we examined antigen-mediated anaphylaxis in Trpc1⁻/⁻ and WT mice, and TRPC1 involvement in the activation of MCs derived from the bone marrow (BMMCs) of these mice. In vivo, we observed a similar induction of passive systemic anaphylaxis in the Trpc1⁻/⁻ mice compared to WT controls. Nevertheless, there was delayed recovery from this response in Trpc1⁻/⁻ mice. Furthermore, contrary to expectations, Trpc1⁻/⁻ BMMCs responded to antigen with enhanced calcium signaling but with little defect in degranulation or associated signaling. In contrast, antigen-mediated production of TNF-α, and other cytokines, was enhanced in the Trpc1⁻/⁻ BMMCs, as were calcium-dependent events required for these responses. Additionally, circulating levels of TNF-α in response to antigen were preferentially elevated in the Trpc1⁻/⁻ mice, and administration of an anti-TNF-α antibody blocked the delay in recovery from anaphylaxis in these mice. These data thus provide evidence that, in this model, TRPC1 promotes recovery from the anaphylactic response by repressing antigen-mediated TNF-α release from MCs.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive MSC 1881, Bethesda, MD 20892-1881, USA.
authors.forename: Nevenka
authors.initials: N
authors.lastname: Medic
authors.forename: Avanti
authors.initials: A
authors.lastname: Desai
authors.forename: Ana
authors.initials: A
authors.lastname: Olivera
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
mesh_terms: D000485:Allergens / Q000276:immunology; D000707:Anaphylaxis / Q000276:immunology*; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D015550:Cell Degranulation / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000485:Allergens; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C096351:transient receptor potential cation channel, subfamily C, member 1