Upregulation of the apoptosis-related inflammasome in cardiac allograft rejection.
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.
Seto
Tatsuichiro
T
Department of Surgery (II), School of Medicine, Shinshu University, Matsumoto, Japan.
Kamijo
Shinobu
S
Wada
Yuko
Y
Yamaura
Kazuhiro
K
Takahashi
Kohei
K
Komatsu
Kazunori
K
Otsu
Yoshinori
Y
Terasaki
Takamitsu
T
Fukui
Daisuke
D
Amano
Jun
J
Taniguchi
Shun'ichiro
S
Sagara
Junji
J
Ito
Ken-ichi
K
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology; D016027:Heart Transplantation / Q000473:pathology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; C498534:Pycard protein, mouse; D012333:RNA, Messenger