IL-33 down-regulates human mast-cell (MC) activation by reprogramming cell signaling

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIAID	IMMUNO/INFLAM-12

Authors

• M Jung
• MA Beaven
• G Bandara
• A Desai
• D Smrz
• T Ito
• DD Metcalfe
• AM Gilfillan

Abstract

IL-33 is reportedly elevated in asthmatic lungs and has been proposed to play a role in the pathogenesis of atopic diseases. However, despite reports that it potentiates antigen/IgE-mediated MC activation in culture, IL-33 did not enhance antigen- induced anaphylaxis in a mouse model. This disparity may reflect the acute nature of the cell based studies that may not mimic the effects of chronic exposure to IL-33 expected in disease states in vivo. We thus examined the long term effects of IL-33 on MC function and observed that, in contrast to short term exposure of mouse and human MCs to IL-33, >72 h exposure dramatically reduces antigen-mediated degranulation and generation of specific cytokines. This downregulated phenotype was not due to reduced expression of the high affinity IgE receptor, FceRI, or KIT. However, examination of critical signaling events, revealed that IL-33 down-regulated the expression and activation of PLCg1 by >75%, thereby producing a marked attenuation of the calcium signal required for degranulation and production of specific cytokines. These data thus reveal that MCs can be epigenetically reprogrammed to produce a hypo-responsive phenotype. The ability to manipulate MC activation in this manner may provide a novel approach for therapeutic intervention of MC-driven disease.

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