NF-κB is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB has long been considered a prototypical proinflammatory signaling pathway, largely based on the activation of NF-κB by proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor α (TNFα), and the role of NF-κB in the expression of other proinflammatory genes including cytokines, chemokines, and adhesion molecules, which has been extensively reviewed. Plant Hormetic compounds such as phytonutrients like polyphenols can inhibit NFK-b thus have an anti inflammatory effect on the body.
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Modification of the Nrf-2 and NF-kB signaling pathways by phytochemicals upregulates antioxidant and detoxification enzymes and suppresses inflammation. The Nrf2 pathway can be activated by the phytochemical sulforaphane in at least two ways, one involving interaction of sulforaphane with the SHs between Keap1 and Nrf2, and the other involving phosphorylation of Nrf2. Once freed from Keap1, Nrf2 translocates into the nucleus, where it induces the expression of genes encoding proteins involved in glutathione synthesis, antioxidant enzymes, phase 2 detoxification enzymes, and proteins involved in NADPH synthesis. Oxidative stress and ligands for TNFRs and TLRs activate upstream IKKs, resulting in phosphorylation of IkB that is normally bound to the inactive NF-kB dimer (p50 and p65) in the cytoplasm. IkB is then targeted for proteasomal degradation and NF-kB then moves into the nucleus, where it induces the expression of inflammatory cytokines as well as genes encoding proteins such as SOD2 and Bcl2 involved in adaptive stress responses. Curcumin can inhibit NF-kB in inflammatory immune cells, whereas other phytochemicals may activate NF-kB in some cell types (e.g., neurons) to enhance stress resistance. ARE, antioxidant response element; IKK, Ik-B kinase; Maf, musculoaponeurotic fibrosarcoma oncogene homolog; NEMO, NF-kB essential modulator; NLS, nuclear localization signal; TLR, Toll-like receptor; TNFR, tumor necrosis factor receptor; Ub, ubiquitin.
Stimulation of microglia, the resident macrophages in the brain, initiates an inflammatory cascade, which involves NF-κB signaling. NF-κB is a ubiquitous transcription factor found in almost all animal cell types. NF-κB regulates the expression of many cytokines and chemokines, such as interferons, interleukins, lymphokines and tumor necrosis factors. Microglial cells express membrane receptors as toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain proteins (NLRs), the receptor for advanced glycation endproducts, RAGE and receptor for interferons and cytokines (Figuera-Losada et al., 2014). TLRs recognize pro-inflammatory ligands such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (Figure 1). PAMPs include bacterial, fungal, parasitic, and viral molecules such as α- and β-glucans, viral RNA and DNA, flagellin, chitin, and microbial cell wall components (Figuera-Losada et al., 2014). DAMPs include blood-clotting factors, RNA, DNA and a variety of intracellular proteins released from damaged and dying cells (Figuera-Losada et al., 2014).
Many plant polyphenolic compounds including curcumin, apigenin, quercetin, (E)-cinnamaldehyde and (E) -resveratrol have been shown to have anti-inflammatory activities in cell culture studies (Gautam and Jachak, 2009). Molecular targets of plant polyphenols acting as anti-inflammatory compounds include arachidonic acid (AA) dependent pathways and AA independent pathways. In the AA-dependent pathway, the anti-inflammatory effect of plant polyphenols is related to their ability to inhibit COX (the isoform Cox-2, also regulated by NF-κB), which converts AA into prostaglandins. AA-independent pathways involve AA signaling through nuclear factor-kappa B (NF-κB) (Yoon and Baek, 2005).
Polyphenols have been shown to interfere at two specific sites in the pathway leading from receptors to NF-kB. Some polyphenols inhibit kinases by inhibiting their phosphorylation or ubiquitination and therefore prevent the subsequent degradation of IkB (Ruiz and Haller, 2006). This prevents NF-κB translocation into the nucleus and transcription of pro-inflammatory cytokines. Additionally, inhibition of the interaction of NF-κB subunits with target DNA has also been proposed as a mode of action of anti-inflammatory polyphenols (Ruiz and Haller, 2006). Both modes of action ultimately lead to the inhibition of expression of various NF-κB regulated pro-inflammatory proteins (cytokines, chemokines) and enzymes (iNOS, COX-2).
Among the polyphenols that have been shown to modulate pro-inflammatory gene expression are curcumin (Jobin et al., 1999), apigenin (Wang et al., 2014), resveratrol (Kundu et al., 2006), quercetin (Endale et al., 2013), silymarin (Saliou et al., 1998) cinnamaldehyde (Reddy et al., 2004), pathenolode (Saadane et al., 2007), ergolide (Chun et al., 2007), 2β,5-epoxy-5,10-dihydroxy-6α-angeloyloxy-9β-isobutyloxy-germacran-8α,12-olide (Lee et al., 2011), andalusol (Heras et al., 1999), ent-kaur-16-ene-19-oic acid (Wu et al., 2013), kamebanin (Hwang et al., 2001), kamebacetal A (Hwang et al., 2001), kamebakaurin (Hwang et al., 2001), excisanin A (Hwang et al., 2001), hypoestoxide(Ojo-Amaize et al., 2001), helenalin (Lyss et al., 1997), pristimerin (Tiedemann et al., 2009), epigallocatechin gallate (Kim et al., 2010), avicin (Haridas et al., 2001), capsaicin (Singh et al., 1996), and oleandrin (Sreenivasan et al., 2003), just to name a few. In this opinion paper, we will focus on curcumin as the prime example as the manuscript format does not allow to elaborate on the specific targets of each of the compounds in the NF-κB pathway.