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Rho Protein Inhibition Blocks Cyclooxygenase-2 Expression by Proinflammatory Mediators in Endothelial Cells

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Abstract

Rho proteins participate in the regulation of inflammatory gene expression in endothelial cells. We made use of Clostridium difficile toxin B-10643 (TcdB-10463) which inhibites RhoA/Rac1/Cdc42 to analyze their role in expression and regulation of cyclooxygenase-2 (COX-2) in endothelial cells (EC). Pretreatment of EC with TcdB-10643 prevented lipopolysaccharide (LPS)- or tumor necrosis factor-α (TNFα )-related COX-2 expression but had no effect on COX-1 protein levels. TcdB-10463 preincubation suppressed LPS-dependent nuclear factor-κB activation (NF-κ B). Rho inhibition did not affect COX-1 activity. Inactivation of Rho proteins before LPS stimulation blocked arachidonic acid (AA)-, thrombin-, and Escherichia coli hemolysin (HlyA)-dependent release of COX-2-related 6-ketoprostaglandin F1α (6k-PGF1α). In contrast, Rho inhibition did not affect COX-2-dependent 6k-PGF1α liberation when TcdB-10643 was added 10 h after LPS or TNFα stimulation of EC. Therefore, RhoA/Rac1/Cdc42 contribute to NF-κ B-dependent LPS- and TNFα-induced expression of PGHS-2 in EC but had no effect on the activity of expressed COX-1 and COX-2.

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Authors and Affiliations

  1. Charité, Department of Internal Medicine, Humboldt-University, Berlin, Germany

    Bernd Schmeck, Marco Brunsch, Joachim Seybold, Matthias Krüll, Norbert Suttorp & Stefan Hippenstiel

  2. Institute of Medical Microbiology, Johannes-Gutenberg-University, Mainz, Germany

    Christoph v. Eichel-Streiber

Authors
  1. Bernd Schmeck
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  2. Marco Brunsch
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  3. Joachim Seybold
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  4. Matthias Krüll
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  7. Stefan Hippenstiel
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Correspondence to Stefan Hippenstiel.

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Schmeck, B., Brunsch, M., Seybold, J. et al. Rho Protein Inhibition Blocks Cyclooxygenase-2 Expression by Proinflammatory Mediators in Endothelial Cells. Inflammation 27, 89–95 (2003). https://doi.org/10.1023/A:1023278600596

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