Leukotriene D(4) induces AP-1 but not NFkappaB signaling in intestinal epithelial cells

Prostaglandins Other Lipid Mediat. 2008 Mar;85(3-4):100-6. doi: 10.1016/j.prostaglandins.2007.11.001. Epub 2007 Nov 12.


We have previously shown that leukotriene D(4) (LTD(4)), a known pro-inflammatory mediator, induces increased survival and proliferation of intestinal epithelial cells. In this study we examined whether LTD(4) functions via activation of the transcription factors NFkappaB and AP-1, which are potent inducers of mitogenesis. We found that the NFkappaB inhibitory protein IkappaBalpha was not degraded upon LTD(4) stimulation. Furthermore, nuclear translocation of the classical p65 or alternative p52 subunits of NFkappaB was not observed. Accordingly, LTD(4) stimulation failed to induce NFkappaB transcriptional activity. Instead we found that LTD(4) induced phosphorylation of c-Jun-N-terminal kinase (JNK) and transcriptional activity of AP-1, which could be reduced by a JNK inhibitor. Moreover, LTD(4) induced cell proliferation, and this effect was also blocked upon addition of a JNK inhibitor. Our findings show for the first time that JNK/AP-1 but not NFkappaB is a downstream target of LTD(4) in intestinal epithelial cells, suggesting that AP-1 is an important mediator of LTD(4)-induced mitogenic effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Humans
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / physiology*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / physiology
  • Leukotriene D4 / pharmacology*
  • NF-kappa B / physiology*
  • Signal Transduction / drug effects*
  • Transcription Factor AP-1 / biosynthesis*


  • NF-kappa B
  • Transcription Factor AP-1
  • Leukotriene D4
  • JNK Mitogen-Activated Protein Kinases