Fas activates the JNK pathway in human colonic epithelial cells: lack of a direct role in apoptosis

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 276; no. 3; pp. G599 - G605
• Main Authors: Abreu-Martin, M T, Palladino, A A, Faris, M, Carramanzana, N M, Nel, A E, Targan, S R
• Format: Journal Article
• Language: English
• Published: United States 01.03.1999
• Subjects: Apoptosis - physiology; Calcium-Calmodulin-Dependent Protein Kinases - physiology; Cell Nucleus - metabolism; Colon - drug effects; Colon - metabolism; Colon - pathology; Fas Ligand Protein; fas Receptor - physiology; Genes, Dominant; Humans; Interferon-gamma - pharmacology; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; JNK Mitogen-Activated Protein Kinases; Membrane Glycoproteins - physiology; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Protein Kinases - genetics; Protein Kinases - metabolism; Transcription Factor AP-1 - metabolism; Tumor Cells, Cultured
• ISSN: 0002-9513; 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.1999.276.3.g599

Fas is expressed constitutively by colonic epithelial cells, and its ligand is expressed by intraepithelial and lamina propria lymphocytes. Fas ligation induces apoptosis in colonic epithelial cells and is implicated in the epithelial damage seen in ulcerative colitis. To understand the pleiotropic effects of Fas in the intestinal mucosa, we have examined signaling pathways activated by Fas in HT-29 colonic epithelial cells. HT-29 cells were stimulated with anti-Fas in the presence or absence of interferon-gamma (IFN-gamma). Activation of mitogen-activated protein kinase pathways was assessed by kinase assay, Western blots, and promoter-reporter assays. Electromobility shift assays were used to assess activator protein-1 (AP-1) binding activity. IFN-gamma increases expression of Fas on HT-29 cells. Signaling via Fas receptor, as determined by induction of c-Jun NH2-terminal kinase (JNK) activity and transcriptional activation of AP-1, is enhanced in IFN-gamma-primed cells. Dominant-interfering mutants of the JNK pathway do not block Fas-mediated apoptosis. Signaling through Fas results in activation of JNK and AP-1 binding activity that is increased in the presence of IFN-gamma. Inhibition of JNK does not block Fas-mediated apoptosis in these cells. Fas-Fas ligand interactions in the intestinal mucosa may lead to complex signal transduction cascades and gene regulation that culminate in apoptosis, cytokine secretion, or other novel functions.