Sustained oxidative stress inhibits NF-κB activation partially via inactivating the proteasome

Abstract

NF-κB is a family of important transcription factors involved in many cellular functions, such as cell survival, proliferation and stress responses. Many studies indicate that NF-κB is a stress sensitive transcription factor and its activation is regulated by reactive oxygen species. In previous studies, we and others demonstrated that this transcription factor can be activated by transient oxidative stress. However, the effects of sustained oxidative stress on NF-κB activation are not clear. The objective of this study is to determine the effects of sustained oxidative stress on NF-κB activation and to elucidate the signaling events affected by sustained oxidative stress. Human lens epithelial cells (HLEC) that were subjected to 4 h of continuous influx of hydrogen peroxide were used to investigate the effects of sustained oxidative stress on NF-κB activation. The data showed that, unlike transient oxidative stress, sustained exposure of HLEC to physiologically relevant levels of H 2 O 2 (50-100 μM for 4) did not induce the degradation of I-κB and activation of NF-κB, but attenuated TNFα-induced degradation of I-κB and activation of NF-κB. Sustained exposure of HLEC to these levels of H 2 O 2 also inactivated proteasome activity by 50-80%. Consistent with the role of the proteasome in degradation of I-κB and activation of NF-κB, treatment of HLEC with proteasome inhibitors also attenuated TNFα-induced I-κB degradation and NF-κB activation. The data also indicate that activation of NF-κB is essential for the cells to recover from oxidative stress. Inhibiting NF-κB activation during recovery from transient oxidative stress significantly reduced the cell viability. Together, these data indicate that sustained oxidative stress may inactivate the proteasome and subsequently inhibit NF-κB activation via impeding the degradation of I-κB. The oxidative inactivation of the proteasome and subsequent impairment of NF-κB activation may contribute to the death of lens epithelial cells, a common feature associated with cataract.

Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling

“…Contradictory studies (6,10) suggest that ROS may either activate or inhibit NF-B, indicating perhaps a dual effect of these oxidants on the signaling pathways that mediate NF-B activation. While higher concentrations of H 2 O 2 have been suggested not to cause NF-B activation and may even lead to its inhibition, lower concentrations may actually stimulate NF-B activity (64). Using a luciferase reporter, we showed that physiologic concentrations of H 2 O 2 led to NF-B activation in ARVM, while pretreatment with APN significantly attenuated NF-B activity.…”

Redox Regulation of Tumor Necrosis Factor Signaling

“…The dose of H 2 O 2 and delivery method may a play a role in the activation or inhibition of NF-kB in cells (30). Similarly, TNF induction of NF-kB activation was shown to require ROS in some cells (60,134), whereas ROS were shown to inhibit TNF-stimulated NF-kB activity in other cells (159,167). In most cells, high doses of ROS are likely to inhibit NF-kB, because of redox inhibition of many proteins involved in NF-kB activation, such as IKK.…”

Heat-shock protein 90 alpha (HSP90α) modulates signaling pathways towards tolerance of oxidative stress and enhanced survival of hepatocytes of Mugil cephalus

“…Because NF-κB is also known to be activated during oxidative stress (Dias et al 2005;Wu et al 2009), in the current study, its expression pattern was analyzed to determine its influence on the survival of pollutant-stressed hepatocytes. Together with ERK1/2, JNK1/2, and Akt, NF-κB activation was determined by using the immunoblotting in the hepatocyte cytosolic and nuclear fractions.…”