title: Inflammatory response to liver fluke Opisthorchis viverrini in mice depends on host master coregulator MTA1, a marker for parasite-induced cholangiocarcinoma in humans.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Biochemistry and Molecular Biology, George Washington University, Washington, DC 20016, USA.
authors: Sujit S
authors: SS
authors: Nair
authors: Anitha
authors: A
authors: Bommana
authors: Suresh B
authors: SB
authors: Pakala
authors: Kazufumi
authors: K
authors: Ohshiro
authors: Amanda J
authors: AJ
authors: Lyon
authors: Sutas
authors: S
authors: Suttiprapa
authors: Maria V
authors: MV
authors: Periago
authors: Thewarach
authors: T
authors: Laha
authors: Peter J
authors: PJ
authors: Hotez
authors: Jeffrey M
authors: JM
authors: Bethony
authors: Banchob
authors: B
authors: Sripa
authors: Paul J
authors: PJ
authors: Brindley
authors: Rakesh
authors: R
authors: Kumar
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000032:analysis; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000469:parasitology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D015415:Biomarkers / Q000032:analysis; D018281:Cholangiocarcinoma / Q000235:genetics / Q000469:parasitology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005210:Fasciola hepatica / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006790:Host-Parasite Interactions / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental; D051379:Mice; D009889:Opisthorchiasis / Q000235:genetics* / Q000503:physiopathology; D009891:Opisthorchis / Q000235:genetics / Q000276:immunology; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D015534:Trans-Activators; D015854:Up-Regulation
chemical_list: D000947:Antigens, Helminth; D015415:Biomarkers; D016207:Cytokines; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D006655:Histone Deacetylases