title: Anti-inflammatory effects of moxifloxacin on activated human monocytic cells: inhibition of NF-kappaB and mitogen-activated protein kinase activation and of synthesis of proinflammatory cytokines.
abstract: 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)-kappaB 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-1beta) 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-kappaB and the mitogen-activated protein kinases ERK and c-Jun N-terminal kinase (JNK). The levels of IL-8, TNF-alpha, and IL-1beta secretion rose 20- and 6.7-fold in lipopolysaccharide (LPS)-activated monocytes and THP-1 cells, respectively. MXF (5 to 20 microg/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-kappaB nuclear translocation increased fourfold following stimulation with LPS-phorbol myristate acetate (PMA), and this was inhibited (38%) by 10 microg of MXF per ml. We then assayed the degradation of inhibitor (I)-kappaB by Western blotting. LPS-PMA induced degradation of I-kappaB by 73%, while addition of MXF (5 microg/ml) inhibited I-kappaB 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 microg/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-kappaB, ERK, and JNK activation. Its anti-inflammatory properties should be further assessed in clinical settings.
authors.affiliation: Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Taly
authors.initials: T
authors.lastname: Weiss
authors.forename: Itamar
authors.initials: I
authors.lastname: Shalit
authors.forename: Hannah
authors.initials: H
authors.lastname: Blau
authors.forename: Sara
authors.initials: S
authors.lastname: Werber
authors.forename: Drora
authors.initials: D
authors.lastname: Halperin
authors.forename: Avital
authors.initials: A
authors.lastname: Levitov
authors.forename: Ina
authors.initials: I
authors.lastname: Fabian
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents; D001372:Aza Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D024841:Fluoroquinolones; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects*; D000077266:Moxifloxacin; D016328:NF-kappa B / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D001372:Aza Compounds; D016207:Cytokines; D024841:Fluoroquinolones; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate; D000077266:Moxifloxacin