Nf Kappa B, the Master Regulator of Inflammation

Nf Kappa B is not your Greek fraternity or sorority…it’s the master regulator of inflammation in your body. Nuclear factor-kappa B (NF-κB) signaling plays a role in not only immunity, but also inflammation, cancer, and nervous system function. As chronic inflammation is at the root of all diseases, it is important to understand what causes it. Learning about Nf Kappa B is a good place to start.

First discovered, over 35 years ago, Nf Kappa B was named for both the DNA (Nuclear Factor Kappa Light chain) and the B-lymphocyte immune cells it impacted. At the time, it was not realized how great a role it played in the activation and development of B cells and inflammation.[i] We have since learned that NF-κB transcription factors regulate inflammation and immune responses, cell growth, cell death (apoptosis), and the expression of certain viral genes.

Because it is not a single protein, but a family of proteins, Nf Kappa B is capable of binding to many target genes based on its form and the presence of other factors. While it has been shown to play a key role in inflammation, it can also be protective. This is due to its selective and complex response.

With an inflammatory stimulus, Nf Kappa B is immediately activated, it moves from the cell cytoplasm to the nucleus, where it binds to specific sequences of DNA, leading to a specific set of responses. Once the stimulus is resolved, it once again becomes latent. Nf Kappa B controls cytokines, which are messengers of the immune response, inflammation, and cell survival. NF-κB affects inflammatory cytokine production as well as chemokines, adhesion molecules, and cell regulation.

On activation, Nf Kappa B stimulates the innate immune system, responsible for our immediate first-line immune response to invaders such as bacteria. If an infection is not resolved and extensive inflammation occurs, Nf Kappa B continues to be involved in our innate immune system, but also then plays a role in our adaptive immune system where both B cells and T cells are activated.

With chronic inflammation, Nf Kappa B continues to stimulate immune cells. Incorrect regulation of Nf Kappa B has been linked to inflammation, cancer, and autoimmune disease.  Inflammation is the hallmark of many diseases including cancer.[ii] NF-κB is activated in many different cancers and has been reported to be overexpressed in 50%-75% of colorectal cancers.[iii] It is known to play a role in mitochondria, our cell’s energy powerhouses, although its exact role in mitochondria function in diseases such as Alzheimer’s and cancer is evolving. [iv]

What are the triggers of Nf Kappa B?

NF-κB is a first responder to harmful substances such as bacteria and viruses. There are many triggers of for NF-κB activity.[v] These include examples such as:

• Viral Infection-Acute respiratory viral inflammation can lead to release of Nf Kappa B and what is referred to as a cytokine storm, which can lead to massive cell destruction and death as seen in a subset of highly pathogenic viruses.[vi]
• Bacterial Infection and Release of Endotoxins called Lipopolysaccharides (LPS)– LPS is released from bacteria or blood from tissues.
• Reactive oxygen species (ROS). ROS as a type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell. A buildup of reactive oxygen species in cells may cause damage to DNA, RNA, and proteins, and may cause cell death. Reactive oxygen species are known as free radicals.
• Tumor necrosis factor alpha (TNFα)-Normal levels keep autoimmune disease and cancer at bay. Healthy people are able to deactivate higher levels of TNFα whereas other individuals may not.
• IL-1β, Pro-inflammatory cytokines-Nf Kappa B can be activated in macrophages, leading to the release of cytokines. Macrophages are characterized by the production of pro-inflammatory cytokines, such as IL-1, IL-6, IL-12, TNF-α and chemokines, involved in various inflammatory processes.[vii]

Examples of What happens when Nf Kappa B is chronically activated:

• Chronic Inflammation– Cytokines that are stimulated by NF-κB, such as TNF-α and IL-1β, are also potent NF-κB inducers, thus establishing a continual loop that can amplify the inflammatory response and lead to chronic inflammation.
• Insulin Resistance and Obesity-Fat tissue has a high concentration of immune cells and when Nf Kappa B is activated, fat cells called adipocytes become inflamed and can lead to inflammation, insulin resistance, and overeating.
• Autoimmune Flares–Higher levels of TNFα are often linked to inflammatory autoimmune conditions such as Rheumatoid Arthritis, Crohn’s disease, and ulcerative colitis.  TNF alpha triggers immune system molecules, including interleukin-1 and interleukin-6. These molecules increase inflammation and can even destroy cartilage and bone, further driving inflammation and flares of autoimmune activity.
• Oxidative Stress-When Reactive Oxygen Species (ROS) known as free radicals exceed anti-oxidant capacity to detoxify them, this results in oxidative stress. Reactive oxygen species can either activate or suppress Nf Kappa B. Activation of the NF-κB pathway can have both anti- and pro-oxidant effects.[viii] Prolonged oxidative stress can result in chronic inflammation, aging and diseases of aging such as heart disease, neurogenerative diseases such as Parkinson’s or Alzheimers, Diabetes, Atherosclerosis, or cancer.

Nf Kappa B Inhibitors

As you might imagine, a great number of research studies have been dedicated to finding substances s to stop the continued release of Nf Kappa B to reduce inflammation. More than 700 inhibitors of the NF-κB activation pathway, including antioxidants, peptides, small RNA/DNA, microbial and viral proteins, small molecules, and engineered polypeptides have been described. Targeting NF-κB seems to be a logical approach to anti-inflammatory therapy. While NF-κB inhibition with specific drugs could be beneficial in treating inflammatory diseases, there are questions about both efficacy and safety, as NF-κB function is also required for maintaining normal immune responses and cell survival.[ix]

A major challenge to developing NF-κB inhibitors for treating various diseases is the ability to target specific pathways or cells and avoid the risk of undesired side effects.[x]  Steroids and NSAIDs have been found to block NF-κB, but their effects lack specificity and thus interfere with NF-κB’s roles in immunity, inflammation, and cellular homeostasis. Aspirin and other salicylates have also been shown to be Nf Kappa B inhibitors. [xi]

There are many clinical trials of Nf Kappa B inhibitors, as well as drugs that have been currently in use given their other properties and have later shown to modulate this pathway also. [xii] This is especially true for small molecules that often participate in multiple modes of action. Identification of established drugs showing additional NF-κB activity has led to the repurposing of drugs for new indications and thus further propelled research in this field. As an example, some drugs such as an anti-malarial drug, mefloquine have been shown in mice studies to have antitumor action through inhibiting NF-κB.[xiii] Vinpocetine was found to inhibit NF-κB induced inflammation in acute ischemic stroke patients.[xiv]

Natural Therapies for Inhibiting Nf Kappa B

A variety of natural substances are known to inhibit Nf Kappa B and, therefore, inflammation. Here are some examples of specific natural inhibitors:

Alpha-lipoic Acid (ALA)-ALA is thought to inhibit LPS, like NAC, through inhibiting Nf Kappa B.[xv] ^,[xvi]ALA was also found to inhibit TNFα.[xvii]

Curcumin and Resveratrol-a flavonoid polyphenol, and resveratrol, a non-flavonoid polyphenol have been found to inhibit Nf Kappa B in adipocytes (fat cells). [xviii] Curcumin Polyphenols may also be useful to prevent or mediate diseases such as Alzheimer’s but further research is needed.[xix]

Flavonoids-Flavonoids are a specific group of bioactive polyphenolic compounds, found abundantly in various fruits, vegetables, beverages (tea, coffee), nuts, and cereal products are known inhibitors. While flavonoid compounds such as quercetin, luteolin, fisetin, apigenin, isoliquiritigenin, rutin, chrysin, silymarin, or kaempferol may serve as Nf Kappa B inhibitors to reduce inflammation in conditions such as cardiovascular disease, weak bioavailability may limit their efficacy.[xx]

Fish-oil and omega 3s-In traumatic brain injury, supplementation with fish oil has been demonstrated to reduce inflammation through inhibiting Nf Kappa B. [xxi] It also has been demonstrated to reduce the metastatic potential of colon cancer cells as well as chronic lymphocytic leukemia. [xxii]^{, [xxiii]} Additionally, it decreases TNF by altering Nf Kappa B activity.[xxiv]

Garlic-Garlic is able to exert activity on cells of inflammation including Nf Kappa B and may be useful as an anti-tumor agent.[xxv]

Green Tea-Green Tea consumption shows uptake in prostate cancer tissue with a decreased activation of Nf Kappa B. [xxvi]

N-acetyl cysteine (NAC)-NAC, a precursor of glutathione (an antioxidant in your body that helps fight free radicals), has been shown to decrease TNF through suppression of Nf Kappa B.[xxvii] It may also reduce cell death from oxidative stress and inflammation in heart failure.[xxviii] NAC has also been shown to be effective in acute lung injury caused by bacterial sepsis and release of LPS.[xxix]

Sulfur-containing compounds, such as methylsulfonylmethane (MSM) were also studied in high glucose-induced inflammation. This inflammation often leads to atherosclerosis, which is considered a major cause of death in type 1 and type 2 diabetic patients.  MSM inhibited the binding of NF-κB protein to the DNA of proinflammatory cytokines, which supported the hypothesis that NF-κB plays a major role in the anti-inflammation ability of sulfur compounds.[xxx]

Photobiomodulation (PBM)-The use of light can remove oxidative stress. Photobiomodulation (PBM) uses light to stimulate cellular mechanisms and facilitate the removal of oxidative stress. PBM reduces oxidative stress and mechanisms that upregulate or downregulate NF-кB, which are critical to tumor progression, insulin dependence or resistance in diabetes, cell proliferation and migration in wound sites, or cell survival through decreasing ROS.[xxxi]  

In summary, here are the key pieces to remember about Nf Kappa B:

• Nf Kappa B is your master regulator of inflammation
• Many drugs are being studied to target inhibiting Nf Kappa for treatment of disease but much is to be learned about the cost/benefit of these drugs
• Natural substances can be used for prevention, symptom management, and reversal of inflammation through inhibiting the Nf Kappa B pathway.
• Given its ability to activate hundreds of genes, much is still to be learned about Nf Kappa B.

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References:

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