Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins.
After autoimmune inflammation, interactions between CD95 and its ligand (CD95L) mediate thyrocyte destruction in Hashimoto's thyroiditis (HT). Conversely, thyroid autoimmune processes that lead to Graves' disease (GD) result in autoantibody-mediated thyrotropin receptor stimulation without thyrocyte depletion. We found that GD thyrocytes expressed CD95 and CD95L in a similar manner to HT thyrocytes, but did not undergo CD95-induced apoptosis either in vivo or in vitro. This pattern was due to the differential production of TH1 and TH2 cytokines. Interferon gamma promoted caspase up-regulation and CD95-induced apoptosis in HT thyrocytes, whereas interleukin 4 and interleukin 10 protected GD thyrocytes by potent up-regulation of cFLIP and Bcl-xL, which prevented CD95-induced apoptosis in sensitized thyrocytes. Thus, modulation of apoptosis-related proteins by TH1 and TH2 cytokines controls thyrocyte survival in thyroid autoimmunity.
Stassi
G
G
Department of Surgical, Anatomical and Oncological Sciences, Human Anatomy Section, University of Palermo, Italy.
Di Liberto
D
D
Todaro
M
M
Zeuner
A
A
Ricci-Vitiani
L
L
Stoppacciaro
A
A
Ruco
L
L
Farina
F
F
Zummo
G
G
De Maria
R
R
D000328:Adult; D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism*; D053222:Fas Ligand Protein; D006111:Graves Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013961:Thyroid Gland / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013967:Thyroiditis, Autoimmune / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051020:bcl-X Protein; D019014:fas Receptor / Q000378:metabolism
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor