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Antimicrobial Agents and Chemotherapy, June 2004, p. 1974-1982, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.1974-1982.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Anti-Inflammatory Effects of Moxifloxacin on Activated Human Monocytic Cells: Inhibition of NF-{kappa}B and Mitogen-Activated Protein Kinase Activation and of Synthesis of Proinflammatory Cytokines

Taly Weiss,1 Itamar Shalit,2 Hannah Blau,2 Sara Werber,1 Drora Halperin,1 Avital Levitov,1 and Ina Fabian1*

Department of Cell Biology and Histology, Sackler School of Medicine,1 Schneider Children's Medical Center of Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel2

Received 15 October 2003/ Returned for modification 18 November 2003/ Accepted 19 February 2004

We previously showed that moxifloxacin (MXF) exerts protective anti-inflammatory effects in immunosuppressed mice infected with Candida albicans by inhibiting interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-{alpha}) production in the lung. Immunohistochemistry demonstrated inhibition of nuclear factor (NF)-{kappa}B translocation in lung epithelium and macrophages in MXF-treated mice. In the present study we investigated the effects of MXF on the production of proinflammatory cytokines (i.e., IL-8, TNF-{alpha}, and IL-1ß) by activated human peripheral blood monocytes and THP-1 cells and analyzed the effects of the drug on the major signal transduction pathways associated with inflammation: NF-{kappa}B and the mitogen-activated protein kinases ERK and c-Jun N-terminal kinase (JNK). The levels of IL-8, TNF-{alpha}, and IL-1ß secretion rose 20- and 6.7-fold in lipopolysaccharide (LPS)-activated monocytes and THP-1 cells, respectively. MXF (5 to 20 µg/ml) significantly inhibited cytokine production by 14 to 80% and 15 to 73% in monocytes and THP-1 cells, respectively. In THP-1 cells, the level of NF-{kappa}B nuclear translocation increased fourfold following stimulation with LPS-phorbol myristate acetate (PMA), and this was inhibited (38%) by 10 µg of MXF per ml. We then assayed the degradation of inhibitor (I)-{kappa}B by Western blotting. LPS-PMA induced degradation of I-{kappa}B by 73%, while addition of MXF (5 µg/ml) inhibited I-{kappa}B degradation by 49%. Activation of ERK1/2 and the 46-kDa p-JNK protein was enhanced by LPS and LPS-PMA and was significantly inhibited by MXF (54 and 42%, respectively, with MXF at 10 µg/ml). We conclude that MXF suppresses the secretion of proinflammatory cytokines in human monocytes and THP-1 cells and that it exerts its anti-inflammatory effects in THP-1 cells by inhibiting NF-{kappa}B, ERK, and JNK activation. Its anti-inflammatory properties should be further assessed in clinical settings.

* Corresponding author. Mailing address: Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Phone: 972-3-6409628. Fax: 972-3-6407432. E-mail: inaf{at}post.tau.ac.il.

Antimicrobial Agents and Chemotherapy, June 2004, p. 1974-1982, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.1974-1982.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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