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Research ArticleToxicology

Trovafloxacin Potentiation of Lipopolysaccharide-Induced Tumor Necrosis Factor Release from RAW 264.7 Cells Requires Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase

Kyle L. Poulsen, Ryan P. Albee, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics May 2014, 349 (2) 185-191; DOI: https://doi.org/10.1124/jpet.113.211276
Kyle L. Poulsen
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan
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Ryan P. Albee
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan
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Patricia E. Ganey
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan
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Robert A. Roth
Department of Pharmacology & Toxicology, Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan
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Abstract

Trovafloxacin (TVX) is a fluoroquinolone antibiotic known to cause idiosyncratic, drug-induced liver injury (IDILI) in humans. The mechanism underlying this toxicity remains unknown. Previously, an animal model of IDILI in mice revealed that TVX synergizes with inflammatory stress from bacterial lipopolysaccharide (LPS) to produce a hepatotoxic interaction. The liver injury required prolongation of the appearance of tumor necrosis factor-α (TNF) in the plasma. The results presented here describe a model of TVX/LPS coexposure in RAW 264.7 cells acting as a surrogate for TNF-releasing cells in vivo. Pretreating cells with TVX for 2 hours before LPS addition led to increased TNF protein release into culture medium in a concentration- and time-dependent manner relative to cells treated with LPS or TVX alone. During the pretreatment period, TVX increased TNF mRNA, but this was less apparent when cells were exposed to TVX after LPS addition, suggesting that the pivotal signaling events that increase TNF expression occurred during the TVX pretreatment period. Indeed, TVX exposure increased activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase. Inhibition of either ERK or JNK decreased the TVX-mediated increase in TNF mRNA and LPS-induced TNF protein release, but p38 inhibition did not. These results demonstrated that the increased TNF appearance from TVX-LPS interaction in vivo can be reproduced in vitro and occurs in an ERK- and JNK-dependent manner.

Footnotes

    • Received November 13, 2013.
    • Accepted February 11, 2014.
  • This study was supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK061315] and National Institutes of Health National Institute of Environmental Health Sciences [Training Grant T32ES007255 (to K.L.P.)].

  • dx.doi.org/10.1124/jpet.113.211276.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 349 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 349, Issue 2
1 May 2014
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Research ArticleToxicology

Trovafloxacin Increases LPS-Induced TNF Release in RAW Cells

Kyle L. Poulsen, Ryan P. Albee, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics May 1, 2014, 349 (2) 185-191; DOI: https://doi.org/10.1124/jpet.113.211276

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Research ArticleToxicology

Trovafloxacin Increases LPS-Induced TNF Release in RAW Cells

Kyle L. Poulsen, Ryan P. Albee, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics May 1, 2014, 349 (2) 185-191; DOI: https://doi.org/10.1124/jpet.113.211276
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