Susceptibility to FAS-induced apoptosis in human nontumoral enterocytes: Role of costimulatory factors

FAS-FAS ligand interaction has been implicated in increased enterocyte apop tosis seen in immune-mediated bowel injury. However, scant information exis ts on the role of FAS in physiological enterocyte turnover. In the present study, the regulation of enterocyte FAS and FAS ligand expression by cytoki nes and its functional role in human intestinal epithelial cell apoptosis a nd proliferation were analyzed with two different models: a nontransformed human intestinal epithelial cell line (HIEC) and normal colonic explant cul tures. HIEC constitutively expressed FAS, as analyzed by flow cytometry. Ho wever, stimulation with agonistic anti-FAS antibody (1-500 ng/ml) did not i nduce HIEC apoptosis. In contrast, in the presence of tumor necrosis factor alpha (TNF alpha) and/or interferon gamma (IFN gamma), HIEC became highly susceptible to PAS-induced apoptosis. The sensitizing effect to FAS-induced apoptosis was mediated via TNF alpha- and IFN gamma-induced upregulation o f FAS expression (maximally 348%). Receptor studies showed that the effect of TNF alpha on FAS was mediated via the p55 TNF receptor. In colonic organ cultures, IFN gamma and TNF alpha also enhanced colonocyte FAS expression, resulting in a markedly increased apoptotic response to stimulation of thi s receptor, as shown by in situ terminal deosyuridine triphosphate nick-end staining. Neither FAS ligand expression nor its induction by cytokines was observed in HIEC or colonic explants. Proliferation studies showed that FA S is not implicated in regulating HIEC growth. These findings suggest that, despite the fact that normal human enterocytes express FAS, costimulatory factors, such as TNF alpha or IFN gamma, abundantly secreted under inflamma tory conditions, are necessary to sensitize intestinal epithelial cells to FAS-induced apoptosis by upregulating this receptor, J. Cell. Physiol. 181: 45-54, 1999. (C) 1999 Wiley-iiss, Inc.