Up-regulation of cyclooxygenase-2 by interleukin-1β in colon carcinoma cells

Growing evidence shows that Interleukin (IL)-1β 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-1β in the human colon carcinoma cell line Caco-2, showing that COX-2 induction by this cytokine is due to both nuclear factor (NF)-κB-dependent transcriptional and p38 mitogen-activated protein kinase (MAPK)-mediated post-transcriptional mechanisms. Treatment of these cells with IL-1β increased the levels of COX-2 mRNA and protein and hence the production of PGE2. IL-1β induced NF-κB activation in Caco-2 cells, promoting the binding of this transcription factor to DNA and increasing NF-κB-dependent transcription. Inhibition of NF-κB activation diminished IL-1β-mediated transcriptional activation of COX-2. Furthermore, mutation or deletion of a putative NF-κB binding site in the human COX-2 promoter greatly diminished its induction by IL-1β. 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-1β. p38 MAPK signalling was required for IL-1β-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-1β.