Regulation of leukotriene-dependent induction of cyclooxygenase-2 and Bcl-2.
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).
Wikström
Katarina
K
Division of Experimental Pathology, Department of Laboratory Medicine, Lund University, University Hospital Malmö, Malmö, Sweden.
Ohd
John F
JF
Sjölander
Anita
A
D018938:Caco-2 Cells; D051546:Cyclooxygenase 2; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D015289:Leukotrienes / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
D007527:Isoenzymes; D015289:Leukotrienes; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D037342:Pertussis Toxin; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases