The role of 12/15-lipoxygenase in the expression of interleukin-6 and tumor necrosis factor-alpha in macrophages

Endocrinology. 2007 Mar;148(3):1313-22. doi: 10.1210/en.2006-0665. Epub 2006 Dec 14.


12/15-lipoxygenase (12/15-LO) enzyme and products have been associated with inflammation and atherosclerosis. However, the mechanism of effects of the 12/15-LO products has not been fully clarified. To study the role of 12/15-LO in cytokine expression, experiments with direct additions of the12/15-LO products, 12(S)-hydroxyeicosa tetraenoic acid or 12(S)-hydroperoxyeicosa-5Z, 8Z, 10E, or 14Z-tetraenoic acid to macrophages were first carried out, and results showed that the 12/15-LO products stimulated mRNA and protein expression of IL-6 and TNF-alpha in a dose-dependent manner. In contrast, an inactive analogue of 12(S)-hydroxyeicosa tetraenoic acid had no effect. To further explore the role of endogenous 12/15-LO in cytokine expression, we used an in vitro and in vivo model to test the effect of 12/15-LO overexpression. The models included Plox-86 cells, a J774A.1 cell line that stably overexpresses leukocyte-type 12/15-LO and primary mouse peritoneal macrophages (MPMs) from 12/15-LO transgenic mice. The results showed a clear increase in IL-6 and TNF-alpha expression in Plox-86 cells and MPMs from 12/15-LO transgenic mice, compared with mock-transfected J774A.1 cells and MPMs from control C57BL6 mice. IL-1beta, IL-12, and monocyte chemoattractant protein (MCP)-1 mRNA were also increased in Plox-86 cells. These data clearly suggest a clear role of 12/15-LO pathway in cytokine production. We also demonstrated that signaling pathways including protein kinase C, p38 MAPK (p38), c-jun NH(2)-terminal kinase as well as nicotinamide adenine dinucleotide phosphate oxidase are important for 12-(S)-hydroxyeicosatetraenoic acid-induced increases in IL-6 and TNF-alpha gene expression. These results suggest a potentially important mechanism linking 12/15-LO activation to chronic inflammation and atherosclerosis.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / pharmacology
  • Animals
  • Arachidonate 12-Lipoxygenase / genetics
  • Arachidonate 12-Lipoxygenase / physiology*
  • Arachidonate 15-Lipoxygenase / genetics
  • Arachidonate 15-Lipoxygenase / physiology*
  • Cells, Cultured
  • Interleukin-6 / metabolism*
  • MAP Kinase Kinase 4 / physiology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • NADPH Oxidases / metabolism
  • Protein Kinase C / physiology
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism*
  • p38 Mitogen-Activated Protein Kinases / physiology


  • 12-15-lipoxygenase
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase
  • NADPH Oxidases
  • Protein Kinase C
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4