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Updated: Jul 19, 2026
In vivo Characterization of Endocrine Disrupting Chemical Effects via Thyroid Hormone Action Indicator Mouse
Published on: October 6, 2023
Anti-apoptotic effects of 3,5,3'-tri-iodothyronine in mouse hepatocytes
1Division of Human Immunology, Signal Transduction Laboratory, Hanson Institute for Cancer Research, IMVS, Adelaide, South Australia 5000, Australia. olga.sukocheva@imvs.sa.gov.au
Abstract:
The present study demonstrates that 3,5,3'-tri-iodothyronine (T3) in physiological dose range inhibits tumor necrosis factor alpha(TNFalpha)/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 TNFalpha/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 TNFalpha-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 TNFalpha/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.
Insights
Physiological doses of 3,5,3'-tri-iodothyronine (T3) protect mouse hepatocytes from tumor necrosis factor alpha (TNFα)/Fas-induced apoptosis. T3 activates protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) pathways, preventing cell death.
Area of Science:
- Hepatology
- Molecular Biology
- Endocrinology
Background:
- Hepatocyte apoptosis is implicated in liver disease pathogenesis.
- Thyroid hormones play crucial roles in cellular functions.
- Tumor necrosis factor alpha (TNFα) and Fas receptor signaling can induce apoptosis in hepatocytes.
Purpose of the Study:
- To investigate the role of 3,5,3 -tri-iodothyronine (T3) in TNFα/Fas-induced hepatocyte apoptosis.
- To elucidate the non-genomic mechanisms underlying T3's potential anti-apoptotic effects.
Main Methods:
- Flow cytometry analysis of annexin V positive cells.
- Assessment of caspase-8 cleavage and DNA fragmentation.
- Measurement of intracellular cAMP, PKA, ERK activation, and intracellular pH.
- Inhibition studies using specific pathway inhibitors (e.g., KT-5720).
- In vivo comparison of hypothyroid and euthyroid mouse models.
Main Results:
- T3 pretreatment inhibited TNFα/Fas-induced apoptosis in mouse hepatocytes.
- T3 attenuated caspase-8 cleavage and DNA fragmentation.
- T3's anti-apoptotic effects were mediated by non-genomic mechanisms involving protein kinase A (PKA) and extracellular signal-regulated kinase (ERK).
- T3 increased intracellular cAMP, activated PKA and ERK, and induced intracellular alkalinization.
- Hepatocytes from hypothyroid mice were more sensitive to TNFα/Fas-induced apoptosis.
Conclusions:
- T3 exerts significant anti-apoptotic effects on hepatocytes through non-genomic signaling pathways.
- The PKA and ERK pathways are critical mediators of T3's protective effects against death receptor-induced apoptosis.
- These findings highlight T3's role in maintaining hepatocyte survival, particularly under inflammatory conditions.
