Functional Fas ligand expression in thyrocytes from patients with Graves' disease.
Fas/Fas ligand (FasL) interaction has been suggested to play a role in the pathogenesis of Hashimoto's thyroiditis. This manuscript addressed a role for Fas/FasL interaction in the pathogenesis of Graves' disease (GD). Apoptosis was detected in 0.5-5.0% of GD thyrocytes, but not in normal thyrocytes from patients with adenoma (N). Fas was constitutively expressed on the basement membrane of both GD and N thyrocytes. Thyrocytes expressed Bcl-2 constitutively in both GD and N thyrocytes. FasL was detected at the messenger ribonucleic acid level in thyroid tissue and cultured thyroid cells by Northern blotting and RT-PCR. FasL protein was detected in the cytoplasm and basolateral surface of thyrocytes from GD, but not in N. Cell surface expression of FasL on cultured thyrocytes disappeared within 48 h after their isolation. However, it was retained by culturing the cells with a matrix metalloproteinase inhibitor. Coculture with thyrocytes induced apoptosis of Fas transfectants, which was blocked by an anti-FasL antibody. Although cultured thyrocytes expressed Fas on the surface, they were not killed by an agonistic anti-Fas antibody. Interferon-gamma-induced Fas up-regulation was suppressed by TSH. These results suggest that the increased expression of FasL in GD thyrocytes, the down-regulation of Fas expression by TSH or possibly by TSH receptor autoantibody, and the overexpression of Bcl-2, which could render thyrocytes resistant to FasL-mediated elimination, may thus be involved in the pathogenesis of GD.
Hiromatsu
Y
Y
Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan. yuji@med.kurume-u.ac.jp
Hoshino
T
T
Yagita
H
H
Koga
M
M
Sakisaka
S
S
Honda
J
J
Yang
D
D
Kayagaki
N
N
Okumura
K
K
Nonaka
K
K
D000328:Adult; D017209:Apoptosis; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005260:Female; D006111:Graves Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D013961:Thyroid Gland / Q000737:chemistry* / Q000166:cytology; D013972:Thyrotropin / Q000494:pharmacology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D007371:Interferon-gamma; D013972:Thyrotropin