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, : P38 MAPK SIGNALING PATHWAY IS INVOLVED IN TRANSFORMING GROWTH FACTOR-beta /SMAD3-INDUCED APOPTOSIS. Digestive Disease Week Abstracts & Itinerary Planner : Abstract No M925

Previously, we have shown that TGF-beta induces apoptosis in rat intestinal epithelial cells (RIE-1) and this effect is mediated by Smad3. However, the downstream pathways involved are unknown. Recently, the mitogen-activated protein kinase (MAPK) pathways have been shown to crosstalk with TGF-beta/Smad pathway to regulate TGF-beta responses. The MAPK family includes extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK. As the newest member of the MAPK family, p38 MAPK is activated in response to inflammatory cytokines, endotoxins and osmotic stress. The upstream steps in its activation are not well defined. The purpose of this study was to determine the role of p38 MAPK in TGF-beta/Smad3-mediated apoptosis in intestinal epithelial cells. Method: RIE-1/Smad3 cell line, generated and characterized by our groups previously, was used in this study. These cells exhibit a six-fold increase in apoptosis after TGF-beta treatment. Cells were pretreated with p38 MAPK inhibitor (SB203580, 0-20 muM) before the addition of TGF-beta (1 ng/ml). TGF-beta transcriptional activity was analyzed using a standard luciferase reporter gene (3TP-Lux). Cell growth was analyzed by counting cells using hemocytometer with trypan blue staining to exclude dead cells, and apoptosis was quantified by DNA fragmentation using cell death detection ELISA kit. Results: When p3TP-Lux was transfected into RIE-1/Smad3 cells, reporter activity was increased five-fold after TGF-beta treatment. This effect was decreased in a dose-dependent fashion when the cells were pretreated with SB 203580 (maximum inhibition was 56%). SB 203580 pretreatment also attenuated the growth inhibitory effect of TGF-beta on RIE-1/Smad3 cells. TGF-beta-induced DNA fragmentation was decreased by 71% following SB 203580 pretreatment. Conclusions: We have shown that p38 MAPK inhibitor, SB 203580, attenuated TGF-beta-induced transcriptional activity, diminished TGF-beta-dependent growth inhibitory effect, and decreased TGF-beta-mediated apoptosis in RIE-1/Smad3 cells. These results indicate that p38 MAPK pathway is involved in TGF-beta/Smad3-mediated signaling and apoptosis. Our results provide evidence for crosstalk between Smad3 and p38 signaling pathways in intestinal epithelial cells.


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