Send to

Choose Destination
See comment in PubMed Commons below
J Hepatol. 2006 Mar;44(3):576-85. Epub 2005 Nov 28.

Immunostimulatory CpG-oligodeoxynucleotides (CpG-ODN) induce early hepatic injury, but provide a late window for protection against endotoxin-mediated liver damage.

Author information

Institute for Clinical and Experimental Surgery, University of Saarland, 66421 Homburg/Saar, Germany.



An impaired immunologic response to infection has been recognized as a major defect in the pathogenesis of sepsis and multi-organ failure. Sepsis-associated liver dysfunction and damage are main determinants for the course of the disease. CpG-motif-containing DNA-sequences (CpG-ODN) were previously shown to confer protection in models of infection by stimulating both innate and specific immune responses. Herein, we studied the effect of CpG-ODN in lipopolysaccharide (LPS)-associated hepatotoxicity.


Sprague Dawley rats pre-treated at day 6 with either CpG-ODN or inert DNA were challenged with E. coli LPS and subsequently studied for liver injury at 6 and 16 h using in vivo fluorescence microscopy and immunohistochemistry. Western blot protein analysis served for assessment of expression of TLR4, TNF receptor-associated factor 6 (TRAF6), NFkappaB and caspase-3. To evaluate CpG-ODN effects during non-septic conditions, additional animals were solely exposed to CpG-ODN and studied after 1 and 6 days.


CpG-ODN application induced marked hepatic microcirculatory deterioration and liver dysfunction at day 1, however, with almost complete recovery to normal at day 6. Interestingly, CpG-ODN pre-treatment decreased LPS-induced leukocyte-endothelial cell interaction, sinusoidal perfusion failure and caspase-3-dependent apoptotic cell death. Although Kupffer cell phagocytic activity was not affected, CpG-ODN pre-treatment in LPS-challenged animals attenuated hepatic protein expression of TRAF6 and NFkappaB and increased TLR4 by almost 100%.


CpG-containing DNA-sequences induce early hepatic injury, but mediate long-term protection against LPS hepatotoxicity. The mechanism of protection is based on the induction of cross-tolerance, probably via inhibition of the downstream TRAF6-NFkappaB signaling pathway and upregulation of the TLR4 surface receptor.

[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center