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  • Title: Anti-apoptotic effects of L-glutamine-mediated transcriptional modulation of the heat shock protein 72 during heat shock.
    Author: Ropeleski MJ, Riehm J, Baer KA, Musch MW, Chang EB.
    Journal: Gastroenterology; 2005 Jul; 129(1):170-84. PubMed ID: 16012946.
    Abstract:
    BACKGROUND & AIMS: During physiologic stress, L-glutamine becomes conditionally essential. Its deficiency results in altered epithelial barrier competence, bacterial translocation, and decreased survival. L-glutamine may attenuate these effects by modulating heat shock protein expression, a well-described effect in vitro. We sought to characterize L-glutamine-dependent transcriptional regulation in heat-shocked intestinal cells and to determine its physiologic relevance. METHODS: IEC-18 and H4 intestinal cells were used. Heat shock protein 72 (Hsp72) gene expression was determined by Northern blotting and luciferase assays. Heat shock factor-1 (HSF-1) activation was assessed by electromobility shift assay, Western blotting, and HSF-1 minimal promoters. Phosphorylation and trimerization of HSF-1 were determined by immunoprecipitation and native nonreducing gradient polyacrylamide gel electrophoresis (PAGE). Camptothecin-induced apoptosis was monitored using caspase-3 and poly (ADP-ribose) polymerase [PARP]-specific antibodies and DNA Elisa +/- Hsp72 siRNA. RESULTS: L-glutamine specifically augmented Hsp72 transcript abundance and HSF-1 DNA binding during heat shock. No glutamine-dependent differences in HSF-1 phosphorylation, trimerization, nuclear localization during heat shock, or HSF-1 minimal promoter activity were observed. Nevertheless, the presence of L-glutamine was an important determinant of wild-type Hsp72 promoter transcriptional activation. Reduced Hsp72 was associated with increased camptothecin-induced caspase-3 and PARP cleavage in glutamine-deficient cells. siRNA treated cells were less resistant to camptothecin. CONCLUSIONS: Taken together, the data suggest that glutamine does not affect the classical pathway of HSF-1 activation and that glutamine-dependent upstream trans -factor binding elsewhere in the Hsp72 promoter or coactivator recruitment may determine Hsp72 abundance. L-glutamine potentiation of Hsp72 is associated with increased epithelial resistance to apoptotic injury.
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