ERK1/2 antagonize AMPK-dependent regulation of Fc epsilon RI-mediated mast cell activation and anaphylaxis

Title
ERK1/2 antagonize AMPK-dependent regulation of Fc epsilon RI-mediated mast cell activation and anaphylaxis
Author(s)
장현욱황승락유예이선김용득조유숙[조유숙]이윤주[이윤주]강원구[강원구]Yoshitaka Taketomi[Yoshitaka Taketomi]문태철[문태철]손종근장영동
Keywords
PROTEIN-KINASE; DEGRANULATION; PATHWAYS; RECEPTOR; RESPONSES; RELEASE; ANTIGEN; ROLES
Issue Date
201409
Publisher
MOSBY-ELSEVIER
Citation
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, v.134, no.3, pp.714 - +
Abstract
Background: Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on Fc epsilon RI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK-mediated negative regulation of Fc epsilon RI signaling in mast cells. Objective: We investigated possible interactions between ERK1/2 and AMPK in the modulation of mast cell signaling and anaphylaxis. Methods: Wild-type or AMPK alpha 2(-/-) mice, or bone marrow-derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to evaluate the functional interplay between ERK1/2 and AMPK in Fc epsilon RI-dependent signaling. Results: The ERK1/2 pathway inhibitor U0126 and the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside similarly inhibited Fc epsilon RI-mediated mast cell signals in vitro and anaphylaxis in vivo. ERK1/2-specific small interfering RNA also mimicked this effect on FceRI signals. Moreover, AMPK alpha 2 knockdown or deficiency led to increased Fc epsilon RI-mediated mast cell activation and anaphylaxis that were insensitive to U0126 or activator 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside, suggesting that the suppression of Fc epsilon RI signals by the inhibition of the ERK1/2 pathway relies largely on AMPK activation. ERK1/2 controlled AMPK activity by regulating its subcellular translocation. Conclusions: ERK1/2 ablated the AMPK-dependent negative regulatory axis, thereby activating FceRI signals in mast cells.
URI
http://hdl.handle.net/YU.REPOSITORY/30839http://dx.doi.org/10.1016/j.jaci.2014.05.001
ISSN
0091-6749
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약학대학 > 약학부 > Articles
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