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J Allergy Clin Immunol. 2016 Apr;137(4):1226-1235. doi: 10.1016/j.jaci.2015.08.052. Epub 2015 Nov 11.

Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock.

Author information

1
Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
2
Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
3
Department of Dermatology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
4
Department of Pathology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
5
Department of Clinical and Laboratory Medicine, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
6
Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan.
7
Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
8
Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan; Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan. Electronic address: anakao@yamanashi.ac.jp.

Abstract

BACKGROUND:

The circadian clock temporally gates signaling through the high-affinity IgE receptor (FcεRI) in mast cells, thereby generating a marked day/night variation in allergic reactions. Thus manipulation of the molecular clock in mast cells might have therapeutic potential for IgE-mediated allergic reactions.

OBJECTIVE:

We determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling was reduced (ie, when core circadian protein period 2 [PER2] is upregulated) resulted in suppression of IgE-mediated allergic reactions.

METHODS:

We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase 1δ/ε, or glucocorticoid, both of which upregulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo.

RESULTS:

PF670462 or corticosterone (or dexamethasone) suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils and passive cutaneous anaphylactic reactions in mice in association with increased PER2 levels in mast cells or basophils. PF670462 or dexamethasone also ameliorated allergic symptoms in a mouse model of allergic rhinitis and downregulated allergen-specific basophil reactivity in patients with allergic rhinitis.

CONCLUSION:

Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases. Additionally, this study suggests a novel mechanism underlying the antiallergic actions of glucocorticoids that relies on the circadian clock, which might provide a novel insight into the pharmacology of this drug in allergic patients.

KEYWORDS:

Circadian clock; IgE; allergy; basophils; mast cells

PMID:
26559325
DOI:
10.1016/j.jaci.2015.08.052
[Indexed for MEDLINE]

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