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Inflammatory response to liver fluke Opisthorchis viverrini in mice depends on host master coregulator MTA1, a marker for parasite‐induced cholangiocarcinoma in humans
Author(s) -
Nair Sujit S.,
Bommana Anitha,
Pakala Suresh B.,
Ohshiro Kazufumi,
Lyon Amanda J.,
Suttiprapa Sutas,
Periago Maria V.,
Laha Thewarach,
Hotez Peter J.,
Bethony Jeffrey M.,
Sripa Banchob,
Brindley Paul J.,
Kumar Rakesh
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24518
Subject(s) - opisthorchis viverrini , biology , inflammation , fibrosis , pathology , liver fluke , immunostaining , carcinogenesis , opisthorchiasis , immunohistochemistry , immunology , gene , medicine , helminths , biochemistry
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. (H EPATOLOGY 2011;)