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Originally published online as doi:10.1189/jlb.0303104 on August 1, 2003

Published online before print August 1, 2003
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(Journal of Leukocyte Biology. 2003;74:908-915.)
© 2003 by Society for Leukocyte Biology

Antibiotic cyclic AMP signaling by "primed" leukocytes confers anti-inflammatory cytoprotection

Kazuhiro Abeyama*,1, Ko-ichi Kawahara*, Satoshi Iino*, Takashi Hamada*, Shin-ichiro Arimura*, Kenji Matsushita{dagger}, Toshihiro Nakajima{ddagger} and Ikuro Maruyama*,1

Departments of
* Laboratory and Molecular Medicine, Faculty of Medicine, and
{dagger} Operative Dentistry and Endodontology, Dental School, Kagoshima University, Japan; and
{ddagger} Department of Genome Science, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan

1Correspondence: Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, Japan, 890-8520. E-mail: k-abeyam{at}m3.kufm.kagoshima-u.ac.jp

The mechanism underlying anti-inflammatory effects of macrolide antibiotics remains uncertain. In this study, we first show the evidences concerning the possible link between leukocytic cyclic adenosine monophosphate (cAMP) signaling and the mechanism of anti-inflammatory, cytoprotective actions of macrolides. The clinical range of macrolides (i.e., erythromycin, roxithromycin, and clarithromycin) preferentially inhibited nuclear factor-{kappa}B activation mediated by reactive oxygen intermediates, inducing cAMP-dependent signaling [i.e., cAMP and cAMP-responsive element-binding protein (CREB)] by "primed" but not "resting" leukocytes. In this context, cAMP/CREB inhibition with adenosine 3':5'-cyclic monophosphothioate, rp-isomer (rp-cAMPs) and CREB decoy oligonucleotides reduced the anti-inflammatory actions of macrolides. These results thus indicate that macrolide-induced cAMP/CREB signaling, selectively by primed leukocytes, plays a major role in the mechanism of anti-inflammatory actions of macrolides.

Key Words: NF-{kappa}B • cytokines • transcriptional factors • signal transduction • reactive oxygen intermediates (ROI)




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