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Abstract
In most tissues, cells are exposed to frequent changes in levels of oxidative stress
and inflammation. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor-κB
(NF-κB) are the two key transcription factors that regulate cellular responses to
oxidative stress and inflammation respectively. Pharmacological and genetic studies
suggest that there is functional cross-talk between these two important pathways.
The absence of Nrf2 can exacerbate NF-κB activity leading to increased cytokine production,
whereas NF-κB can modulate Nrf2 transcription and activity, having both positive and
negative effects on the target gene expression. This review focuses on the potentially
complex molecular mechanisms that link the Nrf2 and NF-κB pathways and the importance
of designing more effective therapeutic strategies to prevent or treat a broad range
of neurological disorders.
Constitutively activated NF-kappaB occurs in many inflammatory and tumor tissues. Does it interfere with anti-inflammatory or anti-tumor signaling pathway? Here, we report that NF-kappaB p65 subunit repressed the Nrf2-antioxidant response element (ARE) pathway at transcriptional level. In the cells where NF-kappaB and Nrf2 were simultaneously activated, p65 unidirectionally antagonized the transcriptional activity of Nrf2. In the p65-overexpressing cells, the ARE-dependent expression of heme oxygenase-1 was strongly suppressed. However, p65 inhibited the ARE-driven gene transcription in a way that was independent of its own transcriptional activity. Two mechanisms were found to coordinate the p65-mediated repression of ARE: (1) p65 selectively deprives CREB binding protein (CBP) from Nrf2 by competitive interaction with the CH1-KIX domain of CBP, which results in inactivation of Nrf2. The inactivation depends on PKA catalytic subunit-mediated phosphorylation of p65 at S276. (2) p65 promotes recruitment of histone deacetylase 3 (HDAC3), the corepressor, to ARE by facilitating the interaction of HDAC3 with either CBP or MafK, leading to local histone hypoacetylation. This investigation revealed the participation of NF-kappaB p65 in the negative regulation of Nrf2-ARE signaling, and might provide a new insight into a possible role of NF-kappaB in suppressing the expression of anti-inflammatory or anti-tumor genes.
Glutathione (GSH) significantly declines in the aging rat liver. Because GSH levels are partly a reflection of its synthetic capacity, we measured the levels and activity of gamma-glutamylcysteine ligase (GCL), the rate-controlling enzyme in GSH synthesis. With age, both the catalytic (GCLC) and modulatory (GCLM) subunits of GCL decreased by 47% and 52%, respectively (P < 0.005). Concomitant with lower subunit levels, GCL activity also declined by 53% (P < 0.05). Because nuclear factor erythroid2-related factor 2 (Nrf2) governs basal and inducible GCLC and GCLM expression by means of the antioxidant response element (ARE), we hypothesized that aging results in dysregulation of Nrf2-mediated GCL expression. We observed an approximately 50% age-related loss in total (P < 0.001) and nuclear (P < 0.0001) Nrf2 levels, which suggests attenuation in Nrf2-dependent gene transcription. By using gel-shift and supershift assays, a marked reduction in Nrf2/ARE binding in old vs. young rats was noted. To determine whether the constitutive loss of Nrf2 transcriptional activity also affects the inducible nature of Nrf2 nuclear translocation, old rats were treated with (R)-alpha-lipoic acid (LA; 40 mg/kg i.p. up to 48 h), a disulfide compound shown to induce Nrf2 activation in vitro and improve GSH levels in vivo. LA administration increased nuclear Nrf2 levels in old rats after 12 h. LA also induced Nrf2 binding to the ARE, and, consequently, higher GCLC levels and GCL activity were observed 24 h after LA injection. Thus, the age-related loss in GSH synthesis may be caused by dysregulation of ARE-mediated gene expression, but chemoprotective agents, like LA, can attenuate this loss.
Introduction Diabetes is one of the most debilitating conditions in patients affecting a substantial proportion of the world's population. Diabetes can predispose an individual to metabolic, cardiovascular disturbances and obesity, and these pathologies are accompanied by vascular complications [1]. Hyperglycaemia-induced damage to the endothelial cells results in micro-vascular complications of the diabetes such as diabetic neuropathy, nephropathy and retinopathy and macro-vascular complications such as cardiomyopathy [2]. Diabetic neuropathy remains the most severe form of complication affecting 40–50% of people with both types of diabetes. The clinical features of diabetic neuropathy range from sensory deficit to allodynia and hyperalgesia. Diabetic neuropathy arises from the long term effects of hyperglycaemia induced damage to peripheral nervous tissue as well as the vasa nervorum [3]. The current knowledge of pathophysiological mechanisms of hyperglycaemia-induced diabetic neuropathy is substantial and recent advances made in field could lead to the development of some novel therapeutic strategies targeted at advance glycation end products (AGE), sorbitol accumulation, protein kinase C (PKC) activation and hexosamine pathway. The axis of pathophysiological factors responsible for diabetes and diabetic neuropathy converge at two of the most extensively studied pathways, oxidative–nitrosative stress and neuroinflammation (Fig. 1). Molecular studies have revealed the involvement of transcriptional regulators such as Nrf2-Keap1 and the NF-κB inflammatory cascade in the pathophysiology of many diseases [4]. NF-κB has been shown to respond to the cellular redox status since a reducing environment prevents its activation whereas oxidative/nitrosative stress promotes phosphorylation and degradation of IκB [5]. Nrf2 increases intracellular GSH levels and GSH-dependent enzymes favouring a reducing environment thereby inhibiting NF-κB. Li et al. demonstrated that Nrf2-deficient mice exhibit greater induction of pro-inflammatory genes regulated by NF-κB such as interleukins, TNF-α, iNOS and COX-2 pointing towards the fact that Nrf2 deficiency enhances NF-κB-mediated pro-inflammatory reactions [6]. Soares et al. showed that HO-1 inhibited the TNF-α dependent activation of NF-κB in endothelial cells. It has been postulated that HO-1 induced by the Nrf2-EpRE interaction inhibits the NF-κB dependent transcriptional apparatus. Inhibition of NF-κB downstream of IκB phosphorylation/degradation and nuclear translocation has been hypothesized to be the site of action of HO-1 [11]. These data further support the concept that the Nrf2 directed increase in the expression of HO-1 is one of the hubs for cross-talk between Nrf2 and NF-κB (Figs. 2 and 3). Recent studies have shown that NF-κB suppresses the transcriptional activity of Nrf2. Liu et al. demonstrated that NF-κB p65 subunit repressed the beneficial effects of Nrf2 by promoting the localisation of transcription repressors, histone deacetylases with Nrf2/ARE and sequestering coactivators like CREB binding protein (CBP) [12]. Cells over-expressing NF-κB showed lesser expression of HO-1 which further confirms that NF-κB activation can act as a repressor of Nrf2 transcriptional activity. In a recent study, Yu et al. found that the N-terminal region of p65 subunit of NF-κB was physically associated with Keap1, and thus provide an additional mechanism for Nrf2–ARE inhibition. It was also suggested that NF-κB not only interacted with cytosolic Keap1 but also promoted nuclear translocation of Keap1 [13]. Previous studies with agents like curcumin [17], melatonin [18], resveratrol [19] and sulphoraphane [20] have reported beneficial effects in ameliorating various functional (motor nerve conduction velocity and nerve blood flow), sensorimotor (thermal and mechanical hyperalgesia) and biochemical deficits in experimental diabetic neuropathy (Fig. 4). These agents also suppressed the increased activity and levels of NF-κB and associated proteins and hence protected against neuroinflammation in diabetic neuropathy. As expected, treatment with these agents increased the levels of Nrf2 and HO-1 which further modulating the redox regulation of pro-inflammatory signalling pathways. Additional studies to find any common co-activators or co-repressors shared by these transcription factors and co-regulation by upstream and downstream signalling in these cascades will enable a better appreciation of the crosstalk between these two transcription factors in diabetic neuropathy. In summary, Nrf2 and NF-κB individually affect many signalling cascades to maintain a redox homeostasis; additionally they interact with each other to further modulate level of key redox modulators in health and disease. Studies with specific agents that might regulate the crosstalk between the two central pleiotropic transcription factors, Nrf2 and NF-κB, may be one of the prospective strategies that might aid in finding newer therapeutic choices for prevention and treatment of diabetic neuropathy.
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