Induction of salivary gland epithelial cell injury in Sjogren's syndrome: in vitro assessment of T cell-derived cytokines and Fas protein expression.
Sjogren's syndrome (SS) is an exocrinopathy characterized by T cell infiltrates, salivary gland epithelial cell (SGEC) apoptosis and high Fas and FasL expression. To address the participation of T cell-derived cytokines and of Fas apoptotic pathway in SS glandular lesions, we utilized non-neoplastic SGEC lines established from SS patients and controls. Possibly attesting to their intrinsic activation, cell lines derived from SS patients displayed significantly higher constitutive Fas and FasL than controls. Surface co-expression of Fas and FasL was not associated with spontaneous fratricide apoptosis. SGEC were resistant to anti-Fas-mediated apoptosis (possibly owing to the constitutive expression of anti-apoptotic proteins cFLIP and Bcl-2), but became sensitive after protein or RNA synthesis inhibition. IFN-gamma and TNF-alpha were able to upregulate surface Fas and FasL, whereas IL-1beta downregulated surface FasL. IFN-gamma (but not several other cytokines) reduced the survival of SGEC in a dose- and time-dependent manner and induced Fas/FasL-mediated apoptosis, directly and via anoikia. Dexamethasone inhibited the upregulation of Fas and FasL by IFN-gamma and the induction of SGEC apoptosis and detachment by anti-Fas mAb or IFN-gamma. Our findings indicate the injurious role of IFN-gamma for the salivary epithelia of SS patients through the induction of Fas-mediated apoptosis and anoikia.
Abu-Helu
R F
RF
Laboratory of Immunology, Department of Pathophysiology, School of Medicine, National University of Athens, Greece.
Dimitriou
I D
ID
Kapsogeorgou
E K
EK
Moutsopoulos
H M
HM
Manoussakis
M N
MN
D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D053222:Fas Ligand Protein; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D012469:Salivary Glands / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D012859:Sjogren's Syndrome / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D019014:fas Receptor / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D003907:Dexamethasone; D007371:Interferon-gamma