Regulation of leukotriene-dependent induction of cyclooxygenase-2 and Bcl-2

Biochem Biophys Res Commun. 2003 Mar 7;302(2):330-5. doi: 10.1016/s0006-291x(03)00187-6.

Abstract

Leukotrienes play an important pathophysiological role in chronic inflammatory states and, as previously shown, cause increased levels of cyclooxygenase-2 (COX-2) in intestinal epithelial cells. The anti-apoptotic protein Bcl-2 is also elevated by LTD(4) stimulation, and in colon cancer, so we studied the mechanisms of COX-2 and Bcl-2 regulation. We found that LTD(4) induced a 3-fold elevation of COX-2 transcription in Int 407 cells and a 2-fold equivalent in colon cancer cells, Caco-2. This was mediated through a pertussis toxin (PTX) sensitive G-protein and the MAP kinase Erk-1/2 pathway, and this was also shown to be the route to up-regulation of Bcl-2 by LTD(4). In good agreement with this, we detected a strong activation of Erk-1/2 that was further increased by COX-2 inhibition, pointing towards the existence of negative feedback regulation. Furthermore, COX-2 activity is responsible for the effects on Bcl-2, but this is not conveyed through the production of PGE(2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Cyclooxygenase 2
  • Drug Interactions
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Humans
  • Isoenzymes / biosynthesis*
  • Isoenzymes / genetics
  • Leukotrienes / pharmacology*
  • MAP Kinase Kinase 1
  • Membrane Proteins
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Pertussis Toxin / pharmacology
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Signal Transduction / physiology*
  • Transcription, Genetic / drug effects
  • Up-Regulation

Substances

  • Isoenzymes
  • Leukotrienes
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Pertussis Toxin
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases