Involvement of Kupffer cell-dependent signaling in T3-induced hepatocyte proliferation in vivo.


Thyroid hormone-induced calorigenesis triggers liver oxidative stress with concomitant TNF-alpha production by Kupffer cells and up-regulation of gene expression. Considering that cyclin-dependent kinase-2 (CDK-2) performs essential functions for cellular proliferation, our aim was to test the hypothesis that l-3,3',5-triiodothyronine (T(3)) stimulates liver cell proliferation by upstream mechanisms involving CDK-2 expression dependent on Kupffer cell signaling. T(3) administration induced a calorigenic response at 60-70 h after treatment, with increased TNF-alpha generation and hepatic oxidative stress status, as shown by enhanced protein carbonyls and decreased glutathione content compared to controls. In this time interval, liver c-jun N-terminal kinase (JNK) phosphorylation, activator protein-1 (AP-1) DNA binding, and CDK-2 expression were enhanced, with concomitantly higher levels of the proliferation markers Ki-67 and proliferating cell nuclear antigen. These changes are abolished by administration of the Kupffer cell inactivator gadolinium chloride prior to T(3) treatment. We conclude that T(3) administration triggers liver CDK-2 expression and cellular proliferation through a cascade associated with Kupffer cell-dependent TNF-alpha generation, JNK phosphorylation, and AP-1 activation. Since CDK-2 promotes phase S progression within the cell cycle, this response may constitute a major mechanism involved in T(3)-induced liver preconditioning to ischemia/reperfusion injury.

Cite this paper

@article{Fernndez2007InvolvementOK, title={Involvement of Kupffer cell-dependent signaling in T3-induced hepatocyte proliferation in vivo.}, author={Virginia V. Fern{\'a}ndez and Solange Reyes and Sergio Bravo and Rodrigo Viana Sep{\'u}lveda and Pamela Romanque and Gonzalo Santander and Iv{\'a}n Castillo and Patr{\'i}cia Varela and Gladys S Tapia and Luis A. Videla}, journal={Biological chemistry}, year={2007}, volume={388 8}, pages={831-7} }