Toll-like receptor 3 signaling attenuates liver regeneration.
The current model for liver regeneration suggests that cell damage triggers Toll-like receptor (TLR) signaling via MyD88, leading to the induction of nuclear factor kappaB (NF-kappaB) and secretion of inflammatory cytokines that in turn prime liver regeneration. TLR3 is unique among TLRs in that it signals through TRIF (TIR domain-containing adaptor-inducing interferon-beta), not through MyD88, and may lead to activation of either the inflammatory or apoptotic pathway. The inflammatory pathway leads to NF-kappaB activation, whereas the apoptotic pathway, believed to be mediated by Rip3, leads to caspase-8 activation. In this study, we explored the role of TLR3 in liver regeneration by comparing the response to 70% partial hepatectomy of TLR3(wt) and TLR3(-/-) mice. We found that following partial hepatectomy, TLR3(-/-) mice demonstrated earlier hepatocyte proliferation. Furthermore, within the first hours, we observed a dramatic TLR3-dependent NF-kappaB activation and an increase in Rip3 levels in hepatocytes, accompanied by caspase-8 activation but without an apoptotic outcome.


CONCLUSIONS
TLR3 plays an inhibitory role in the priming of liver regeneration, thus reinforcing the role of the innate immune system in balancing tissue regeneration.
Goldyne Savad Institute for Gene Therapy, Human Biology Research Center Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Elina
E
Zorde-Khvalevsky
Rinat
R
Abramovitch
Hila
H
Barash
Irit
I
Spivak-Pohis
Ludmila
L
Rivkin
Jacob
J
Rachmilewitz
Eithan
E
Galun
Hilla
H
Giladi
D000818:Animals; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000502:physiology*
D051196:Toll-Like Receptor 3