title: Functional Fas ligand expression in thyrocytes from patients with Graves' disease.
abstract: 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.
authors.affiliation: Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan. yuji@med.kurume-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Hiromatsu
authors.forename: T
authors.initials: T
authors.lastname: Hoshino
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: M
authors.initials: M
authors.lastname: Koga
authors.forename: S
authors.initials: S
authors.lastname: Sakisaka
authors.forename: J
authors.initials: J
authors.lastname: Honda
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.forename: N
authors.initials: N
authors.lastname: Kayagaki
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: K
authors.initials: K
authors.lastname: Nonaka
mesh_terms: 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
chemical_list: 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