title: Induction and regulation of Fas-mediated apoptosis in human thyroid epithelial cells.
abstract: Fas-mediated apoptosis has been proposed to play an important role in the pathogenesis of Hashimoto's thyroiditis. Normal thyroid cells are resistant to Fas-mediated apoptosis in vitro but can be sensitized by the unique combination of interferon-gamma and IL-1beta cytokines. We sought to examine the mechanism of this sensitization and apoptosis signaling in primary human thyroid cells. Without the addition of cytokines, agonist anti-Fas antibody treatment of the thyroid cells resulted in the cleavage of proximal caspases, but this did not lead to the activation of caspase 7 and caspase 3. Apoptosis associated with the cleavage of caspases 7, 3, and Bid, and the activation of mitochondria in response to anti-Fas antibody occurred only after cytokine pretreatment. Cell surface expression of Fas, the cytoplasmic concentrations of procaspases 7, 8, and 10, and the proapoptotic molecule Bid were markedly enhanced by the presence of the cytokines. In contrast, P44/p42 MAPK (Erk) appeared to provide protection from Fas-mediated apoptosis because an MAPK kinase inhibitor (U0126) sensitized thyroid cells to anti-Fas antibody. In conclusion, Fas signaling is blocked in normal thyroid cells at a point after the activation of proximal caspases. Interferon-gamma/IL-1beta pretreatment sensitizes human thyroid cells to Fas-mediated apoptosis in a complex manner that overcomes this blockade through increased expression of cell surface Fas receptor, increases in proapoptotic molecules that result in mitochondrial activation, and late caspase cleavage. This process involves Bcl-2 family proteins and appears to be compatible with type II apoptosis regulation.
authors.affiliation: Department of Medicine, University of Michigan Medical Center, 9220 Medical Sciences Research Building III, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0648, USA.
authors.forename: Emese
authors.initials: E
authors.lastname: Mezosi
authors.forename: Su He
authors.initials: SH
authors.lastname: Wang
authors.forename: Saho
authors.initials: S
authors.lastname: Utsugi
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bajnok
authors.forename: James D
authors.initials: JD
authors.lastname: Bretz
authors.forename: Paul G
authors.initials: PG
authors.lastname: Gauger
authors.forename: Norman W
authors.initials: NW
authors.lastname: Thompson
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D019014:fas Receptor / Q000737:chemistry* / Q000502:physiology
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002070:Butadienes; D002352:Carrier Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; C113580:U 0126; D019014:fas Receptor; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012260:Ribonucleases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases