Up-regulation of cyclooxygenase-2 by interleukin-1beta in colon carcinoma cells.
Growing evidence shows that Interleukin (IL)-1beta and Cyclooxygenase 2 (COX-2) play a crucial role in the pathogenesis of inflammatory diseases and tumor growth, particularly in the gastrointestinal tract. Here, we have analyzed the regulation of COX-2 by IL-1beta in the human colon carcinoma cell line Caco-2, showing that COX-2 induction by this cytokine is due to both nuclear factor (NF)-kappaB-dependent transcriptional and p38 mitogen-activated protein kinase (MAPK)-mediated post-transcriptional mechanisms. Treatment of these cells with IL-1beta increased the levels of COX-2 mRNA and protein and hence the production of PGE2. IL-1beta induced NF-kappaB activation in Caco-2 cells, promoting the binding of this transcription factor to DNA and increasing NF-kappaB-dependent transcription. Inhibition of NF-kappaB activation diminished IL-1beta-mediated transcriptional activation of COX-2. Furthermore, mutation or deletion of a putative NF-kappaB binding site in the human COX-2 promoter greatly diminished its induction by IL-1beta. In addition, this cytokine induced a rapid increase in p38 MAPK activation. Interestingly, inhibition of p38 MAPK by SB203580 severely decreased induction of COX-2 expression by IL-1beta. p38 MAPK signalling was required for IL-1beta-dependent stabilization of COX-2 transcript. Given the importance of COX-2 expression in intestinal inflammation and colon carcinogenesis, these findings contribute to determine the key signalling pathways involved in the regulation of COX-2 expression in colorectal cells by inflammatory stimuli, such as IL-1beta.
Duque
Javier
J
Centro de Biología Molecular "Severo Ochoa", Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Díaz-Muñoz
Manuel D
MD
Fresno
Manuel
M
Iñiguez
Miguel A
MA
D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000201:enzymology*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases