Rebuilding the balance of STAT1 and STAT3 signalings by fusaruside, a cerebroside compound, for the treatment of T-cell-mediated fulminant hepatitis in mice.
Dysregulation of signal transducer and activator of transcription (STAT) signaling is usually associated with intricate immune diseases and rebuilding the balance of STAT1 and STAT3 signaling is being explored as a useful approach for the treatment of these diseases. However, few chemicals have been reported to rebuild the balance of these two signalings for immune hepatitis therapy. In the present study, we found that fusaruside, a new kind of cerebroside isolated from an endophytic fungus Fusarium sp. IFB-121 in Quercus variabilis, significantly ameliorated concanavalin A (Con A)-induced T-cell-mediated fulminant hepatitis in mice, which was closely associated with the improvement of histopathological parameters, inhibition of activation of liver CD4(+) T cells and NKT cells, regulation of balance of Th1/Th2/Th17/Treg cytokines and protection of hepatocyte from apoptosis. Moreover, T-cell proliferation and activation was also notably inhibited by fusaruside in vitro. Furthermore, the protective effect of fusaruside was attributable to a novel regulatory mechanism through down-regulating STAT1 activation and T-bet expression in liver CD4(+) T cells and up-regulating STAT3 activation and Bcl-X(L) expression in hepatocytes. In conclusion, fusaruside exhibited its capability against T-cell-mediated liver injury in vivo, through rebuilding the balance of STAT1 and STAT3 signalings. These results suggest that fusaruside is potentially useful for the treatment of T-cell-mediated human liver disorders.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Xing-Xin
XX
Wu
Yang
Y
Sun
Wen-Jie
WJ
Guo
Yan-Hong
YH
Gu
Xue-Feng
XF
Wu
Ren-Xiang
RX
Tan
Qiang
Q
Xu
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002554:Cerebrosides / Q000302:isolation & purification / Q000494:pharmacology*; D003208:Concanavalin A; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005670:Fusarium / Q000737:chemistry; D006520:Hepatitis, Animal / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050795:STAT2 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051020:bcl-X Protein / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D015704:CD4 Antigens; D002554:Cerebrosides; D016207:Cytokines; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; D051020:bcl-X Protein; C576678:fusaruside; D003208:Concanavalin A