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Hepatology. 2011 Oct;54(4):1388-97. doi: 10.1002/hep.24518. Epub 2011 Sep 6.

Inflammatory response to liver fluke Opisthorchis viverrini in mice depends on host master coregulator MTA1, a marker for parasite-induced cholangiocarcinoma in humans.

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  • 1Department of Biochemistry and Molecular Biology, George Washington University, Washington, DC 20016, USA.

Abstract

Based on the recently established role for the master coregulator MTA1 and MTA1-containing nuclear remodeling complexes in oncogenesis and inflammation, we explored the links between parasitism by the carcinogenic liver fluke Opisthorchis viverrini and this coregulator using both an Mta1(-/-) mouse model of infection and a tissue microarray of liver fluke-induced human cholangiocarcinomas (CCAs). Intense foci of inflammation and periductal fibrosis in the liver and kidneys of wild-type Mta1(+/+) mice were evident at 23 days postinfection with O. viverrini. In contrast, little inflammatory response was observed in the same organs of infected Mta1(-/-) mice. Livers of infected Mta1(+/+) mice revealed strong up-regulation of fibrosis-associated markers such as cytokeratins 18 and 19 and annexin 2, as determined both by immunostaining and by reverse-transcription polymerase chain reaction compared with infected Mta1(-/-) mice. CD4 expression was up-regulated by infection in the livers of both experimental groups; however, its levels were several-fold higher in the Mta1(+/+) mice than in infected Mta1(-/-) mice. Mta1(-/-) infected mice also exhibited significantly higher systemic and hepatic levels of host cytokines such as interleukin (IL)-12p70, IL-10, and interferon-γ compared with the levels of these cytokines in the Mta1(+/+) mice, suggesting an essential role of MTA1 in the cross-regulation of the Th1 and Th2 responses, presumably due to chromatin remodeling of the target chromatin genes. Immunohistochemical analysis of ≈ 300 liver tissue cores from confirmed cases of O. viverrini-induced CCA showed that MTA1 expression was elevated in >80% of the specimens.

CONCLUSION:

These findings suggest that MTA1 status plays an important role in conferring an optimal cytokine response in mice following infection with O. viverrini and is a major player in parasite-induced CCA in humans.

Copyright © 2011 American Association for the Study of Liver Diseases.

PMID:
21725997
[PubMed - indexed for MEDLINE]
PMCID:
PMC3184196
Free PMC Article
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