Moxifloxacin inhibits cytokine-induced MAP kinase and NF-kappaB activation as well as nitric oxide synthesis in a human respiratory epithelial cell line.
BACKGROUND
We previously demonstrated that the quinolone moxifloxacin prevents Candida albicans pneumonitis and epithelial nuclear factor kappaB (NF-kappaB) nuclear translocation in immunosuppressed mice.


OBJECTIVE
To explore the anti-inflammatory effects of moxifloxacin directly on a lung epithelial cell line.


METHODS
We studied the effect of clinically relevant concentrations of moxifloxacin (2.5-10 mg/L) on cytokine-induced activation of nitric oxide (NO) secretion, inducible NO synthase (iNOS) expression and the activation of signal transduction pathways of inflammation, NF-kappaB and the mitogen-activated protein kinases [extracellular signal-regulated kinases (ERK1/2) and C-Jun N-terminal kinase (JNK)], in the A549 lung epithelial cell line.


RESULTS
Stimulation with the cytokines interleukin-1beta(IL-1beta)/interferon-gamma (IFN-gamma) increased NO up to 3.3-fold and moxifloxacin inhibited this up to 68% (P < 0.05). Similarly, the increase in iNOS levels was inhibited in cells pre-treated with moxifloxacin by up to 62%. IL-1beta stimulated a rapid increase in the activities of early intracellular signalling molecules, ERK1/2 and JNK. Moxifloxacin inhibited ERK1/2 by up to 100% and p-JNK activation by 100%. NF-kappaB, as measured by electrophoretic mobility shift assay, was inhibited up to 72% by moxifloxacin. Western-blot analysis revealed that IL-1beta enhanced NF-kappaB p65 and p50 proteins by 1.7- and 3.6-fold, respectively, whereas moxifloxacin inhibited the proteins by up to 60%.


CONCLUSIONS
Moxifloxacin inhibits intracellular signalling, iNOS expression and NO secretion in a lung epithelial cell line. Future studies may uncover a primary site of quinolone immunomodulation, either upstream or at the cell membrane. Eventually, this quinolone might become an important therapy for inflammatory lung diseases.
Werber
Sara
S
Department of Cell Biology and Histology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Shalit
Itamar
I
Fabian
Ina
I
Steuer
Guy
G
Weiss
Taly
T
Blau
Hannah
H
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D024841:Fluoroquinolones; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000077266:Moxifloxacin; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D011804:Quinolines / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D001372:Aza Compounds; D016207:Cytokines; D024841:Fluoroquinolones; D016328:NF-kappa B; D011804:Quinolines; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D000077266:Moxifloxacin