Document Detail

Induction and regulation of Fas-mediated apoptosis in human thyroid epithelial cells.
MedLine Citation:
PMID:  15563545     Owner:  NLM     Status:  MEDLINE    
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.
Emese Mezosi; Su He Wang; Saho Utsugi; Laszlo Bajnok; James D Bretz; Paul G Gauger; Norman W Thompson; James R Baker
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.     Date:  2004-11-24
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  19     ISSN:  0888-8809     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-02-24     Completed Date:  2005-06-28     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  804-11     Citation Subset:  IM    
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.
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MeSH Terms
Antigens, CD95 / chemistry*,  physiology
BH3 Interacting Domain Death Agonist Protein
Butadienes / pharmacology
Carrier Proteins / metabolism
Caspase 3
Caspase 7
Caspases / metabolism
Cell Membrane / metabolism
Cell Survival
Cytokines / metabolism
Enzyme Inhibitors / pharmacology
Epithelial Cells / cytology*
Flow Cytometry
Interferon-gamma / metabolism
Interleukin-1 / metabolism
Mitochondria / metabolism
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Nitriles / pharmacology
Proto-Oncogene Proteins c-bcl-2 / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Ribonucleases / metabolism
Signal Transduction
Thyroid Gland / cytology,  metabolism*,  pathology*
Grant Support
P60DK20572/DK/NIDDK NIH HHS; R01 A137141//PHS HHS
Reg. No./Substance:
0/Antigens, CD95; 0/BH3 Interacting Domain Death Agonist Protein; 0/BID protein, human; 0/Butadienes; 0/Carrier Proteins; 0/Cytokines; 0/Enzyme Inhibitors; 0/Interleukin-1; 0/Nitriles; 0/Proto-Oncogene Proteins c-bcl-2; 0/U 0126; 82115-62-6/Interferon-gamma; EC Protein Kinase 1; EC Protein Kinase 3; EC 3.1.-/Ribonucleases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP7 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7; EC 3.4.22.-/Caspases

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