Abstract
Antagonizing TNF-α and its signaling is proven to be a successful therapeutic strategy in various disease processes. Although blocking TNF-α signaling attenuated the disease activity, the overarching clinical contraindications remains to be a greater concern and reasons for the adverse effects are largely unknown. TNF-α induces ROS and as ROS is pivotal for activation of antioxidant transcription factor, Nrf2, we posit that any impairment in TNF-α signaling could affect Nrf2-dependent basal redox homeostasis. HL-1 cardiomyocytes, TNFR1/2 double knockout mice (DKO) that shows hampered TNF-α signaling were used as experimental models. Electron Paramagnetic Resonance Spectroscopy (EPR) measurements revealed that as low as 2 ng TNF-α/ml, ROS was induced significantly (p10ng/ml in HL-1 cells. TNF-α (2-5 ng /ml, for 2 h) evoked robust (p<0.05, n=3) nuclear translocation of Nrf2 and increased nuclear binding (Trans AM DNA binding analysis) along with significant (p<0.05) induction in trans-activation of Nrf2 targets. Additionally, this was associated with 2-fold increase (p<0.05) in intracellular glutathione (GSH) that is associated with significant cell death only at higher (>10 - 50 ng/ml) and later time points (12 h and 24 h). These results suggest that TNF-α mediated ROS induction activates Nrf2 dependent antioxidant system in cardiomyocytes. In vivo experiments with TNFR1/2 DKO demonstrates that the expression of Nrf2-regulated genes were significantly downregulated indicating a weakened antioxidant system. Also, the acute exercise stress (AES) induced Nrf2 trans-activation observed in WT mice was significantly blunted in TNFR1/2 DKO suggesting a need for TNF signaling in stress induced Nrf2 activation. These results support the concept that complete and/or sustained blockade of TNF signaling may result in compromised Nrf2-dependent antioxidant defense in the myocardium. This further necessitates that during chronic anti-TNF-α treatment, a finely tuned and maintenance of specific threshold of TNF-α signaling is essential to avoid oxidant stress based complications in cardiovascular system.
Published Version
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