Bacterial cytolethal distending toxin promotes the development of dysplasia in a model of microbially induced hepatocarcinogenesis.
Bacterial cytolethal distending toxins (CDTs) containing DNase I-like activity can induce limited host DNA damage that leads to activation of the DNA-damage repair responses in cultured cell lines. However, in vivo experimental evidence linking CDTs to carcinogenesis is lacking. In this study, infection of A/JCr mice with an isogenic mutant of Helicobacter hepaticus lacking CDT activity (CDT mutant) induced chronic hepatitis comparable to wild-type H. hepaticus (Hh) infection at both 4 and 10 months post inoculation (MPI); however, the CDT mutant-infected mice did not develop hepatic dysplasic nodules at 10 MPI, whereas those infected with Hh did. There was no significant difference in hepatic colonization levels between the CDT mutant and Hh at both time points (P > 0.05). At 4 MPI, mice infected with Hh had significantly enhanced hepatic transcription of proinflammatory TNF-alpha, IFN-gamma and Cox-2, growth mediators IL-6 and TGF-alpha, anti-apoptotic Bcl-2 and Bcl-X(L), and increased hepatocyte proliferation (P < 0.05) compared with the control or the CDT mutant-infected mice. In addition, Hh infected male mice had upregulated hepatic mRNA levels of RelA (p65), p50, GADD45beta and c-IAP1, components of the NF-kappaB pathway compared with the CDT mutant-infected mice. At 10 MPI, Hh infection was associated with significant upregulation of IL-6 mRNA. Activation of the inflammatory NF-kappaB pathway and upregulation of proinflammatory cytokines plus IL-6 in the Hh but not in the CDT mutant-infected mice suggest that Hh CDT plays a key role in promoting the dysplastic changes in Hh-infected mouse livers.
Ge
Zhongming
Z
Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. zge@mit.edu
Rogers
Arlin B
AB
Feng
Yan
Y
Lee
Amy
A
Xu
Shilu
S
Taylor
Nancy S
NS
Fox
James G
JG
D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D005260:Female; D016481:Helicobacter Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D044923:Helicobacter hepaticus / Q000235:genetics / Q000502:physiology*; D006521:Hepatitis, Chronic / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D022781:Hepatocytes / Q000382:microbiology / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D008297:Male; D051379:Mice; D009154:Mutation; D015533:Transcriptional Activation
D001427:Bacterial Toxins; C067044:cytolethal distending toxin