title: Antibiotic cyclic AMP signaling by "primed" leukocytes confers anti-inflammatory cytoprotection.
abstract: 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-kappaB 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.
authors.affiliation: Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. k-abeyam@m3.kufm.kagoshima-u.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Abeyama
authors.forename: Ko-ichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iino
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamada
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Arimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsushita
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011650:Pulmonary Alveoli; D020545:Respiratory Mucosa; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D000975:Antioxidants; D017362:Cyclic AMP Response Element-Binding Protein; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016753:Interleukin-10; D000242:Cyclic AMP