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.
Fernández
Virginia
V
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile. vfernand@med.uchile.cl
Reyes
Solange
S
Bravo
Sergio
S
Sepúlveda
Rodrigo
R
Romanque
Pamela
P
Santander
Gonzalo
G
Castillo
Iván
I
Varela
Patricia
P
Tapia
Gladys
G
Videla
Luis A
LA
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019791:Guanidine / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology* / Q000187:drug effects*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014284:Triiodothyronine / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D014284:Triiodothyronine; D004247:DNA; D051357:Cyclin-Dependent Kinase 2; D048031:JNK Mitogen-Activated Protein Kinases; D019791:Guanidine