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Title: In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines.
Authors: Mizuno, Rei
Kamioka, Yuji
Kabashima, Kenji
Imajo, Masamichi  kyouindb  KAKEN_id
Sumiyama, Kenta
Nakasho, Eiji
Ito, Takeshi  orcid (unconfirmed)
Hamazaki, Yoko  kyouindb  KAKEN_id
Okuchi, Yoshihisa
Sakai, Yoshiharu
Kiyokawa, Etsuko
Matsuda, Michiyuki  kyouindb  KAKEN_id  orcid (unconfirmed)
Author's alias: 水野, 礼
松田, 道行
Issue Date: 19-May-2014
Publisher: Rockefeller University Press
Journal title: The Journal of experimental medicine
Abstract: Many chemical mediators regulate neutrophil recruitment to inflammatory sites. Although the actions of each chemical mediator have been demonstrated with neutrophils in vitro, how such chemical mediators act cooperatively or counteractively in vivo remains largely unknown. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Förster resonance energy transfer, we time-lapse-imaged the activities of extracellular signal-regulated kinase (ERK) and protein kinase A (PKA) in neutrophils in inflamed intestinal tissue. ERK activity in neutrophils rapidly increased during spreading on the endothelial cells and showed positive correlation with the migration velocity on endothelial cells or in interstitial tissue. Meanwhile, in the neutrophils migrating in the interstitial tissue, high PKA activity correlated negatively with migration velocity. In contradiction to previous in vitro studies that showed ERK activation by prostaglandin E2 (PGE2) engagement with prostaglandin receptor EP4, intravenous administration of EP4 agonist activated PKA, inhibited ERK, and suppressed migration of neutrophils. The opposite results were obtained using nonsteroidal antiinflammatory drugs (NSAIDs). Therefore, NSAID-induced enteritis may be caused at least partially by the inhibition of EP4 receptor signaling of neutrophils. Our results demonstrate that ERK positively regulates the neutrophil recruitment cascade by promoting adhesion and migration steps.
Description: 生きたマウスの白血球の中で分子活性を可視化することに世界で初めて成功 -非ステロイド性抗炎症薬は白血球を活性化する-. 京都大学プレスリリース. 2014-05-26.
Rights: © 2014 Mizuno et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at
DOI(Published Version): 10.1084/jem.20132112
PubMed ID: 24842369
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