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Introduction: Apoptosis of intestinal epithelial cells (IECs) must be tightly regulated to ensure maintenance of gastrointestinal mucosal integrity. Sphingosine-1-phosphate (S1P) has been shown to play a protective role for the IECs by repressing apoptosis, particularly in response to stressful conditions. The mechanism by which S1P represses apoptosis is unknown. Stress granules (SG) are cytoplasmic aggregates of RNA and protein that are composed of untranslated cell transcripts, and are considered to be a cellular protective entity that forms during times of stress for the cell. The current study examines whether the mechanism of S1P-induced repression of apoptosis was through induction of SG formation. Methods: Studies were performed upon cultured differentiated IECs (IEC-Cdx2L1 line). Western blotting was assessed and siRNA transfections were via Lipofectamine. SG subcellular localization was done by immunofluorescence staining.Results: S1P has been previously shown to repress apoptosis in IEC in response to TNF-alpha/cycloheximide (CHX). Treatment of IECs with S1P (2.5 mcM) increases cytoplasmic accumulation of translational repressor RNA binding protein TIAR by ~10 fold. S1P treatment also increases SG formation (~ 30%) in arsenite-induced cellular stress, as measured by increased eif3b. Both S1P exposure and Induction of SG formation were protective for IECs exposed to apoptotic stimuli, by both number of apoptotis cells (control n=48, SG n= 9) and by Annexin staining. In contrast, silencing of TIA-1 reduced S1P-induced stress granule formation in stressed cells to control levels. Conclusions: These results indicate that S1P represses apoptosis in IEC through increasing accumulation of stress granules.