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Virginia Fernndez, Solange Reyes, Sergio Bravo, Rodrigo Seplveda, Pamela Romanque, Gonzalo Santander, Ivn Castillo, Patricia Varela, Gladys Tapia, Luis A. Videla

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

Keywords: cell proliferation, signal transduction

Thyroid hormone-induced calorigenesis triggers liver oxidative stress with concomitant TNF-α production by Kupffer cells and up-regulation of gene expression. Considering that cyclindependent kinase-2 (CDK-2) performs essential functions for cellular proliferation, our aim was to test the hypothesis that L-3,3',5-triiodothyronine (T₃) stimulates liver proliferation by upstream mechanisms involving CDK-2 expression dependent on Kupffer cell signaling. T₃ administration induced a calorigenic response at 60-70 h after treatment, with increased TNF- α 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 Nterminal kinase (JNK) phosphorylation, activator protein-1 (AP-1) DNA binding, and CDK-2 expression are enhanced, concomitantly with higher levels of the proliferation markers Ki-67 and PCNA. These changes are abolished by administration of the Kupffer cell inactivator gadolinium chloride prior to T₃ treatment. We conclude that T₃ administration triggers liver CDK-2 expression and cellular proliferation through a cascade associated with Kupffer cell-dependent TNF-α 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 T₃-induced liver preconditioning to ischemia/reperfusion injury.

Biological Chemistry, Walter de Gruyter

Print ISSN: 1431-6730
Volume: 2007
Pages: -

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