Upregulation of the apoptosis-related inflammasome in cardiac allograft rejection.

ABSTRACT

BACKGROUND: Inflammation is a major factor in cardiac allograft rejection. Accumulating reports have demonstrated an important role of the inflammation-induced adaptor complex, called the inflammasome, in the field of immunology. The apoptosis-associated, speck-like protein containing a caspase recruitment domain (ASC) is an adaptor protein that forms the inflammasome and regulates caspase-1-dependent generation of inflammatory cytokines. The aim of the present study was to determine how ASC is associated with the development of cardiac allograft rejection. METHODS: We used a murine heterotopic cardiac transplantation model between fully incompatible strains. Donor hearts (n = 9 for each time-point) were harvested for examination on Days 1, 4, 7 and 12 after transplantation. Histopathologic findings of cardiac grafts were evaluated using rejection scores. The expression of ASC and inflammatory cytokines in cardiac grafts were analyzed by immunohistochemistry and real-time reverse transcript-polymerase chain reaction (RT-PCR). RESULTS: Expression levels of both ASC and IL-1 beta were higher in the myocardial interstitium of allografts in parallel to the progress of cardiac rejection during the acute phase after transplantation. In contrast, expression of ASC and IL-1 beta remained low in isografts. Cardiac allografts treated with tacrolimus showed decreased expression of both ASC and IL-1 beta similar to that seen in isografts. Real-time RT-PCR demonstrated similar alteration of ASC and IL-1 beta mRNA expression in cardiac grafts during the acute phase. CONCLUSIONS: Our results demonstrate a novel finding showing that upregulation of ASC is closely associated with the inflammation induced in cardiac grafts after transplantation in the mouse.