Related Experiment Videos
Antibiotic cyclic AMP signaling by "primed" leukocytes confers anti-inflammatory cytoprotection
Kazuhiro Abeyama1, Ko-ichi Kawahara, Satoshi Iino
1Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. k-abeyam@m3.kufm.kagoshima-u.ac.jp
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.
Insights
Macrolide antibiotics reduce inflammation by activating cyclic adenosine monophosphate (cAMP) signaling in primed white blood cells. This pathway, involving cAMP and CREB, is crucial for their anti-inflammatory effects.
Area of Science:
- Pharmacology
- Immunology
- Molecular Biology
Background:
- The precise mechanism of macrolide antibiotics' anti-inflammatory properties is not fully understood.
- Leukocyte signaling pathways, particularly cyclic adenosine monophosphate (cAMP), are implicated in inflammatory responses.
Purpose of the Study:
- To investigate the role of leukocytic cAMP signaling in the anti-inflammatory actions of macrolide antibiotics.
- To elucidate the specific molecular targets and cellular conditions involved in macrolide-mediated anti-inflammation.
Main Methods:
- Macrolides (erythromycin, roxithromycin, clarithromycin) were tested for their effects on nuclear factor-kappaB (NF-κB) activation in primed and resting leukocytes.
- Cyclic adenosine monophosphate (cAMP) and cAMP-responsive element-binding protein (CREB) signaling pathways were analyzed.
- Inhibition of cAMP/CREB signaling was achieved using adenosine 3 ':5 '-cyclic monophosphothioate, rp-isomer (rp-cAMPs) and CREB decoy oligonucleotides.
Main Results:
- Clinical concentrations of macrolides preferentially inhibited NF-κB activation mediated by reactive oxygen species in primed leukocytes.
- Macrolides induced cAMP-dependent signaling, specifically activating cAMP and CREB pathways in primed leukocytes.
- Inhibiting cAMP/CREB signaling with rp-cAMPs and CREB decoy oligonucleotides diminished the anti-inflammatory effects of macrolides.
Conclusions:
- Macrolide-induced activation of the cAMP/CREB signaling pathway in primed leukocytes is a key mechanism underlying their anti-inflammatory effects.
- This study identifies a specific cellular context (primed leukocytes) and molecular pathway (cAMP/CREB) critical for macrolide antibiotic efficacy in reducing inflammation.