Fas/FasL mediated apoptosis of thyrocytes in Graves' disease

We examined in the present study the possible involvement of Fas and its li gand (FasL) in the process of Graves' disease. Immunohistochemical analysis showed that few normal thyrocytes expressed Fas but many thyrocytes in Gra ves' disease expressed this molecule. The percentage of FasL-positive thyro cytes in Graves' thyroids was, however, less than in normal thyroids. Sever al apoptotic thyrocytes and infiltrating mononuclear cells (MNCs) were dete cted scattered throughout Graves' thyroid tissues and abundant proliferatin g cell nuclear antigen (PCNA)-positive thyrocytes were present. Apoptotic c ells, as well as PCNA-positive cells, were scarcely detectable in normal th yroid glands, however. In vitro treatment of thyrocytes by IL-1 beta a cyto kine found to be expressed in Graves' thyroid glands, increased Fas but red uced FasL expression. IL-1 beta -stimulated thyrocytes became sensitive to apoptosis by anti-Fas IgM monoclonal antibody (mAb). Activated T cells, whi ch strongly expressed FasL, showed cytotoxic activity toward IL-1 beta -sti mulated thyrocytes but not toward unstimulated thyrocytes. This cytotoxic a ctivity involved the Fas/FasL pathway. Importantly, unstimulated thyrocytes could kill activated, but not resting, T cells. IL-1 beta -stimulated thyr ocytes, with down-regulated FasL expression, could not efficiently kill act ivated T cells. The cytotoxic activity of unstimulated thyrocytes toward ac tivated T cells was inhibited by anti-FasL mAb. Interestingly, unstimulated thyrocytes induced apoptosis in IL-1 beta -stimulated thyrocytes but not i n unstimulated thyrocytes. These interactions were also blocked by anti-Fas L mAb. Our results suggest that the apoptotic cell death of both thyrocytes and infiltrating MNCs found in Graves' thyroid glands is regulated by IL-1 beta through Fas/FasL interactions.