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D. Miyazaki, S.-I. Sasaki, S. Mihara, T. Tominaga, K. Yakura, Y. Inoue; Pharmacological Inhibition of IB Kinase Aggravates Ocular Allergic Reactions. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1563.
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© ARVO (1962-2015); The Authors (2016-present)
The NFΚB pathway is crucial in activation of innate immune responses, and has also been recognized for roles in tissue homeostasis. Since inhibitors of IΚB or IΚB kinase (IKK) are known to act as anti-inflammatory in innate immune cascade, the effects of inhibition of IΚB or IKK to ocular allergy and their crucial components were assessed using allergen-sensitized mice and cultured mast cells or B cells.
Ragweed pollen-sensitized mice, provoked for acute allergic inflammation by the allergen instillation, were used as in vivo model. Acute phase inflammation was assessed using in vitro isolated mast cells or B cells. Induction of inflammatory cytokines was evaluated by ELISA. Binding activities of NFΚB subunits were profiled using NFΚB binding assay. NFΚB promoter activity was assessed using luciferase assay after transient transfection of NFΚB reporter plasmid.
Unexpectedly, acute inflammatory responses, including mast cell degranulation, were significantly aggravated by IKK inhibition, with significant systemic increase of IL-1β, TNF-α, IL-9, RANTES, IL-2, MCP-1, and MIP-1α, as well as allergen-specific IgE. After screening of inflammatory subsets responsible for this aberrant response, we identified B-220+ cells as major source of unregulated release of inflammatory cytokines. Analysis of splenic B220+ B cells using specific inhibitors or siRNA of each segment of NFΚB cascade indicated that IKKβ inhibition activated NFΚB promoter and NFΚB binding activity. Selective inhibition of IKKβ, but not IKKα, activated B cells to secrete IL-1β and MCP-1. Finally, the activation of mast cell degranulation induced by IKK inhibition in isolated mast cells, as well as in allergen-sensitized mice, was suppressed by IL-1 receptor antagonist treatment.
In ocular allergic reactions, IKK play previously unappreciated roles to limit B cell-mediated mast cell activation and inflammatory cytokine induction.
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