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Division of Human Immunology, Signal Transduction Laboratory, Hanson Institute for Cancer Research, IMVS, Frome Road, Adelaide, South Australia 5000, Australia
¹ Department of Biometry and Statistics, School of Public Health, University at Albany, SUNY, One University Place, Rensselaer, New York 12144, USA

(Requests for offprints should be addressed to O A Sukocheva; Email: olga.sukocheva{at}imvs.sa.gov.au)

The present study demonstrates that 3,5,3'-tri-iodothyronine (T₃) in physiological dose range inhibits tumor necrosis factor (TNF)/Fas-induced apoptosis in mouse hepatocytes. T₃ pretreatment prevented Fas-induced early stage of apoptosis signs assessed by flow cytometry analysis of the annexin V positive cell population. T₃ attenuated TNF/Fas-induced cleavage of caspase-8 and DNA fragmentation. We found that T₃ exerted its anti-apoptotic effects by mobilization of several non-genomic mechanisms independent of transcriptional activity. Inhibition of protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and Na⁺/H⁺ exchanger blocked T₃-dependent anti-apoptotic effects indicating an involvement of these intracellular targets into T₃-induced signaling cascade. Furthermore, physiological concentrations of T₃, but not reverse T₃, caused increases in intracellular cAMP content and activated PKA. T₃ markedly induced phosphorylation of ERK. We also detected T₃-dependent intracellular alkalinization that abolished TNF-induced acidification. PKA inhibitor KT-5720 blocked T₃-induced activation of ERK and intracellular alkalinization confirming the upstream position of PKA signaling. We further detected that hepatocytes from hypothyroid mice are more sensitive to TNF/Fas-induced apoptosis than euthyroid animals in vivo. Together, these findings imply that T₃ triggers PKA- and ERK-regulated intracellular pathways capable of driving and ensuring hepatocytes survival in the presence of death receptor ligand-induced damage under chronic inflammatory conditions.