13-HPODE and 13-HODE modulate cytokine-induced expression of endothelial cell adhesion molecules differently

Biofactors. 1999;9(1):61-72. doi: 10.1002/biof.5520090108.


Expression of cellular adhesion molecules (CAMs) at endothelial surfaces represents a physiological response to vascular damage and mediates the initiation of inflammation and possibly of atherogenesis. The cytokines TNF alpha and IL-1 are potent inducers of CAMs in endothelial cells. Reactive oxygen species comprising lipid oxidation products have been implicated in the signaling pathways of both TNF alpha and IL-1 and accordingly could modulate atherogenic events. We, therefore, investigated the potential role of the lipoxygenase product, 13-hydroperoxyoctadecadienoic acid (13-HPODE), which has also been identified in oxidized low density lipoproteins on CAM expression in HUVEC. 13-HPODE induced the expression of ICAM-1 in a concentration dependent manner up to 75 microM. Higher concentrations were toxic. Similar effects were observed with H2O2 and phosphatidylcholine hydroperoxide. VCAM-1 and E-selectin were not induced by 13-HPODE. 13-HPODE administered simultaneously with IL-1 or TNF alpha induced ICAM-1 additively, suggesting that hydroperoxides and cytokines act on the same signaling pathways. In contrast, pretreatment of cells with 50 microM 13-HPODE for 1 hour rather inhibited subsequent cytokine-induced ICAM-1 and E-selectin expression. Surprisingly, the reduction product of 13-HPODE, 13-hydroxyoctadecadienoic acid (13-HODE) proved to be an even better inducer of ICAM-1 than 13-HPODE. Pretreatment with 13-HODE did not show any inhibitory effect on ICAM-1 expression. Our data show that lipoxygenase products differentially affect CAM expression. 13-HPODE is stimulatory by itself and can positively or negatively affect cytokine signaling depending on time of exposure. 13-HODE induces CAM expression by itself but does not inhibit cytokine signaling. Thus, the interplay of lipoxygenase products with proinflammatory cytokines can not simply be explained by an oxidant-mediated facilitation of cytokine signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion Molecules / metabolism*
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors
  • Cytokines / pharmacology*
  • Dose-Response Relationship, Drug
  • E-Selectin / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Intercellular Adhesion Molecule-1 / metabolism
  • Linoleic Acids / pharmacology*
  • Lipid Peroxides / pharmacology*
  • Phosphatidylcholines / pharmacology
  • Reducing Agents / pharmacology
  • Signal Transduction / drug effects
  • Time Factors
  • Tumor Necrosis Factor-alpha / pharmacology
  • Umbilical Cord / cytology
  • Up-Regulation / drug effects
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Cell Adhesion Molecules
  • Cytokines
  • E-Selectin
  • Linoleic Acids
  • Lipid Peroxides
  • Phosphatidylcholines
  • Reducing Agents
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • phosphatidylcholine hydroperoxide
  • Intercellular Adhesion Molecule-1
  • 13-hydroperoxy-9,11-octadecadienoic acid
  • 13-hydroxy-9,11-octadecadienoic acid
  • Hydrogen Peroxide