Document Detail


Novel role of CD40 in Fas-dependent apoptosis of cultured salivary epithelial cells from patients with Sjögren's syndrome.
MedLine Citation:
PMID:  15692983     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To determine the role of Fas and CD40 in the molecular mechanism of salivary epithelial cell death in Sjogren's syndrome (SS). METHODS: The expression of Fas and CD40 in SS salivary epithelial cells was analyzed by flow cytometry. Induction of apoptosis with anti-Fas and/or anti-CD40 monoclonal antibodies (mAb) was examined by morphologic analysis, DNA fragmentation, and TUNEL assay. Expression of c-FLIP, Fas-associated phosphatase 1, FADD, Bcl-2, Bcl-x(L), and Bcl-x(S) was determined by Western blot analysis. RESULTS: Expression of Fas and CD40 was significantly higher in SS salivary epithelial cells than in normal cells after interferon-gamma (IFNgamma) stimulation (P < 0.001 for both Fas and CD40). Although neither anti-Fas (CH11) nor anti-CD40 mAb alone could induce typical apoptosis, the two together and preincubation with IFNgamma efficiently induced apoptosis in SS salivary epithelial cells. This apoptosis was almost completely blocked by neutralizing anti-Fas mAb (ZB4), whereas an antagonistic mAb to CD40 (ch5D12) partially inhibited anti-Fas/anti-CD40-induced apoptosis. Also, c-FLIP, an important inhibitory molecule in the Fas death pathway, was strongly expressed in SS salivary epithelial cells, but its expression was down-regulated at the protein level by anti-CD40 mAb. CONCLUSION: CD40 signals promote Fas-dependent death of SS salivary epithelial cells by down-regulating c-FLIP expression. The presence of c-FLIP in these cells may explain their resistance to undergoing apoptosis in response to either anti-Fas or anti-CD40 mAb, despite their surface expression of both proteins. These findings suggest that SS salivary epithelial cell death requires the cooperation of both Fas and CD40.
Authors:
Li Ping; Noriyoshi Ogawa; Susumu Sugai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  52     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-02-09     Completed Date:  2005-03-14     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  573-81     Citation Subset:  AIM; IM    
Affiliation:
Kanazawa Medical University, Kahoku-gun, Ishikawa-ken, Japan.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal / pharmacology
Antigens, CD40 / analysis,  immunology,  physiology*
Antigens, CD95 / analysis,  immunology,  physiology*
Apoptosis / physiology*
CASP8 and FADD-Like Apoptosis Regulating Protein
Cells, Cultured
DNA Fragmentation
Down-Regulation
Epithelial Cells / physiology
Female
Flow Cytometry
Humans
In Situ Nick-End Labeling
Interferon-gamma / pharmacology
Intracellular Signaling Peptides and Proteins / analysis
Male
Middle Aged
Salivary Glands / chemistry,  pathology*
Sjogren's Syndrome / pathology,  physiopathology*
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antigens, CD40; 0/Antigens, CD95; 0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/CFLAR protein, human; 0/Intracellular Signaling Peptides and Proteins; 82115-62-6/Interferon-gamma

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