Inflammatory cytokine regulation of Fas-mediated apoptosis in thyroid follicular cells

The occurrence of apoptosis in thyroid follicular cells induced by Fas acti vation has been a subject of much debate. This is due, in part, to the fact that no physiologically relevant treatment conditions have been reported t o cause rapid and extensive Fas-mediated apoptosis in thyroid cells, wherea s treatment with the protein synthesis inhibitor cycloheximide prior to Fas activation allows for massive cell death. This indicates that the Fas sign aling pathway is present but that its function is blocked in the overwhelmi ng majority of cultured thyroid cells. To reconcile the conflicting reports , we set out to identify physiologically relevant conditions in which rapid , massive thyroid cell apoptosis in response to Fas activation could be dem onstrated. We determined that susceptibility to Fas-activated apoptosis cou ld be influenced by certain combinations of inflammatory cytokines. Althoug h no single cytokine was effective, pretreatment of thyroid cells with the combination of gamma-interferon and either tumor necrosis factor-alpha or i nterleukin 1 beta allowed for massive Fas-mediated apoptosis. Susceptibilit y to Fas-induced death correlated with an increase in expression of a tunic amycin-inhibitable high molecular weight form of Fas but not with aggregate expression of Fas.