CsA downregulates IFN-gamma gene transcription after liver transplantation by inhibiting NF-kappa B activity.
OBJECTIVE
To investigate the relationship between NF-kappa B activity and IFN-gamma gene expression, as well as the histopathological changes following liver transplants, both with and without cyclosporin A (CsA) treatment.


METHODS
Sixty male Wistar and Thirty male SD rats were subjected to orthotopic liver transplants. Fourty-five of the Wistar rats were used as recipients, and were divided into 3 groups: group I, syngeneic control (Wistar-to-Wistar); group II, acute rejection (SD-to-Wistar); and group III: acute rejection treated with cyclosporin A by intramuscular injection (SD-to-Wistar + CSA). After the liver transplants, electrophoretic gel mobility shift assay was used to analyze NF-kappa B activity in the splenocytes of recipient rats, and RT-PCR was used to measure IFN-gamma gene expression in grafted liver specimens. In addition, histopathological examinations were performed to assess the severity of acute liver rejection.


RESULTS
In group I, low levels of NF-kappa B activity were only detectable on day 5 and 7 post-transplant, and only weak IFN-gamma mRNA expression was observed at all time points. By contrast, both high NF-kappa B activity and high expression levels of IFN-gamma mRNA were detected at all time points in group II. In group III, NF-kappa B activity and IFN-gamma mRNA expression were significantly inhibited, as compared to group II (P < 0.05). A good correlation was found between NF-kappa B activity and IFN-gamma mRNA expression (r = 0.815). In addition, NF-kappa B activity and IFN-gamma mRNA expression mirrored histopathological changes in all three experimental groups.


CONCLUSIONS
Changes in IFN-gamma mRNA expression levels after liver transplantation are at least partially due to changes in levels of NF-kappa B activity. CsA appears to downregulate NF-kappa B activity, thus inhibiting IFN-gamma gene transcription. Blocking the NF-kappa B mediated transcription pathway may be of benefit in preventing liver transplant rejection.
Jia
Changku
C
Department of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. jiachk@sohu.com
Zheng
Shusen
S
Xie
Haiyang
H
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D015536:Down-Regulation; D015870:Gene Expression; D006084:Graft Rejection / Q000517:prevention & control; D007371:Interferon-gamma / Q000032:analysis / Q000235:genetics*; D016031:Liver Transplantation; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000502:physiology*
D016328:NF-kappa B; D007371:Interferon-gamma; D016572:Cyclosporine