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,**
* Department of Medicine,
Department of Biochemistry and the
** Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, GA 30322
3To whom correspondence should be addressed. E-mail: tzieg01{at}emory.edu.
Epithelial cell apoptosis is an important regulator of normal gut mucosal turnover; however, excessive apoptosis may inhibit mucosal restitution during pathophysiologic states. Apoptosis is induced by oxidative stress and cytokines, but regulation by specific nutrients has been infrequently studied under these conditions. Glutamine (Gln) is an important metabolic fuel for intestinal epithelial cells and a precursor to the antioxidant glutathione (GSH), which has antiapoptotic effects. In cultured intestinal epithelial cells, Gln depletion increases oxidant-induced apoptosis. This study examined whether Gln protects against apoptosis induced by the cytokine tumor necrosis factor-alpha–related apoptosis-inducing ligand (TRAIL) in the human colon carcinoma cell line, HT-29. TRAIL-induced apoptosis in HT-29 cells was characterized by an increase in the percentage of cells in the sub-G1 fraction by flow cytometry, nuclear condensation and the activation of caspase-8 and caspase-3. TRAIL-induced apoptosis was completely prevented by Gln, but not inhibited by other amino acids, including the GSH constituents, glutamate, cysteine and glycine. Similar antiapoptotic effects of Gln occurred when apoptosis was induced by a combination of tumor necrosis factor-alpha and interferon-gamma. Cellular GSH was oxidized during TRAIL-induced apoptosis. This effect was completely blocked by Gln, however, inhibition of GSH synthesis with buthionine sulfoximine did not alter Gln antiapoptotic effects. Furthermore, glutamate prevented GSH oxidation in response to TRAIL but did not protect against TRAIL-induced apoptosis. These results show that Gln specifically protects intestinal epithelial cells against cytokine-induced apoptosis, and that this occurs by a mechanism that is distinct from the protection against oxidative stress mediated by cellular GSH.
KEY WORDS: • apoptosis • cytokines • glutathione • intestine • TRAIL
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