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Involvement of Kupffer cell-dependent signaling in T 3 -induced hepatocyte proliferation in vivo

2007; De Gruyter; Volume: 388; Issue: 8 Linguagem: Inglês

10.1515/bc.2007.101

1437-4315

Virginia Fernández, S. Reyes, Sergio Esteban Ortega Bravo, Rodrígo Sepúlveda, Pamela Romanque, Gonzalo Santander, Iván Castillo, Patricia Varela, Gladys Tapia, Luis A. Videla,

Mitochondrial Function and Pathology

Abstract Thyroid hormone-induced calorigenesis triggers liver oxidative stress with concomitant TNF-α 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-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 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-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 T 3 -induced liver preconditioning to ischemia/reperfusion injury.