There are large white blood cells in the human body called Macrophages. Among several tasks, these “big eaters” (Greek) are responsible for both triggering inflammation as an immune response, and causing an anti-inflammatory response for repairs. But what is inflammation? What does it look like when systemic inflammation goes unchecked? We’ll look at the types of inflammation, how it works, where it is found to influence other conditions and ways to fight it.
Table of Contents
Acute Inflammation:
Inflammation is a defense mechanism in the body. The immune system recognizes damaged cells, irritants, and pathogens, and it begins the healing process. This is generally an acute process, and vital to our health.
i.e. Bee sting, the flu, broken bones.
Chronic Inflammation:
When the cause of inflammation persists, this normally temporary process becomes chronic, with increasing health risks. Elevated levels of inflammatory cytokines such as TNF-a, IL6, IL1b trigger tissue breakdown, destruction and slow loss of function of those organs or systems. They increase DNA damage, breaks, unregulated cell division, cancer growth, and metastasis.
What are Cytokines?
Cytokines are the general name for various small secreted proteins released by cells have a specific effect on the interactions and communications between cells.
There are pro-inflammatory and anti-inflammatory cytokines.
Pro-inflammatory cytokines like TNFa, IL6 & IL1b, are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions.
TheFour Measurable Markers
TNFa
Tumor Necrosis Factor Alpha (TNFa) – has been implicated in a variety of human diseases including Alzheimer’s disease, cancer, major depression, psoriasis and inflammatory bowel disease (IBD). Studies of depression and IBD are currently being linked to TNF levels.
IL6
Interleukin 6 (IL-6) – stimulates the inflammatory and auto-immune processes in many diseases such as diabetes, atherosclerosis, depression, Alzheimer’s Disease, systemic lupus erythematosus, multiple myeloma, prostate cancer, Behçet’s disease, and rheumatoid arthritis.
IL1B
Interleukin 1b (IL1B) – has been associated with elevated anxiety, panic disorders, and an increased risk of cardiovascular disease.
CRP
C-Reactive Protein (CRP) – rises in systemic inflammation. A good predictor of heart disease, heart attack & stroke risk. Also rises in cancer, diabetes, inflammatory bowel disease, and obstructive sleep apnea. Made in the liver.
Inflammatory Response
The body’s response to inflammation is a very complicated process. While much research has led to greater understanding, immunology continues to discover and study its mechanisms.
Understanding markers like cytokines help us in our research to both inhibit inflammation and discover its varied causes.
Next, let’s look at a simplified inflammatory pathway: Arachidonic Acid.
Arachidonic Acid Pathway
Arachidonic acid is a fatty acid within the cell membranes. With its metabolites, it’s considered an intracellular messenger of the inflammatory response. As we study inflammation pathways such as this, we learn which substances help to inhibit inflammatory response.
Scientists have learned which pharmaceutical compounds and dietary changes/supplementations help to inhibit both Arachidonic Acid and its metabolites.
To learn more about this pathway specifically, there are many resources available to get started.
Cardiovascular Inflammation
It is the inflammatory process in your arteries that cause plaque build up and heart attacks and stroke, not cholesterol per se.
Oxidized cholesterol in inflammatory, so is Lp(a), a small dense lipoprotein that is genetic and very damaging to endothelial cells.
Small particles of cholesterol get lodged under endothelial cells in artery. Macrophage immune cells enter the artery lining to gobble them up. They become stuck and are called foam cells. Foam cells produce high levels of inflammatory cytokines.
Your body begins the process of “patching” the problem by forming plaque.
Plaque can become very unstable due to enzymes like Phospholipase.
Unstable plaque is what breaks open and causes strokes and heart attacks.
Statins don’t protect you by lowering cholesterol…they lower inflammation.
Many natural substances we will discuss lower inflammation even better without side effects.
Digestive Inflammation
The cells that line your intestines keep a tight junction to keep bacteria, yeasts, and toxins out of your bloodstream. Many things cause inflammation of the gut lining, enlarging the gaps between the cells in a process commonly termed Leaky Gut.
While scientists are still trying to determine the exact cause of leaky gut syndrome, possible contributing factors include:
- Excessive sugar intake
- Long-term use of NSAIDs
- Excessive alcohol intake
- Nutrient deficiencies
- Chronic inflammation
- Poor gut health
- Gut yeast proliferation
Let’s investigate a few other likely sources of digestive inflammation:
Antibiotics
Probiotics are crucial to help protect against inflammation. Antibiotics also kill your good bacteria, which can allow Candida and Clostridium difficile to thrive.
Carrageenan
Carrageenan creates mucosal inflammation, ulcerations and immune cell activation against your gut lining. It so reliably causes inflammation of tissues that researchers used it to cause inflammation in mice and rats to test potential anti-inflammatory drugs.
PPI’s
Proton Pump Inhibitors (PPI’s) reduce protein breakdown in the stomach, allowing undigested foods to enter the small intestine and ferment and cause inflammation.
Food Sensitivities
For many people, their immune cells in the gut identify certain foods as a threat, and attack them, creating inflammation. If you eat these everyday, a constant state of inflammation exists in the gut.
Metabolic Inflammation
According to the Mayo Clinic, metabolic syndrome is
…a cluster of conditions that occur together, increasing your risk of heart disease, stroke and type 2 diabetes.
These conditions include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.
Just having one of the conditions isn’t an indication of metabolic inflammation, but might be a cause to see your doctor.
The condition is closely linked to obesity, inactivity, and insulin resistance.
Obesity
Fat tissue is now considered to be an active organ that secretes various pro-inflammatory cytokines in obesity and contributes to chronic low-level systemic inflammation. There is a positive correlation between fat cell size and levels of TNF-α, IL-6, and high-sensitivity CRP.
Fatty Liver
Nonalcoholic fatty liver disease (NAFLD) describes a range of disorders characterized by excess accumulation of triglyceride within the liver…Inflammation is believed to be the driving force behind NASH and the progression to fibrosis and subsequent cirrhosis.
Diabetes
High sugar levels cause glycation and inflammation related damage, overproduction of insulin promotes inflammatory growth signals. High insulin and insulin resistance are associated with elevated levels of inflammatory markers and increase the risk of Alzheimer’s disease (AD). Inflammation has been proposed as a key pathogenic factor for AD, often called diabetes of the brain.
Brain Inflammation promotes Alzheimer’s and Parkinson’s
Brain inflammation doesn’t cause pain since the brain has no pain receptors
Instead, research suggests it raises risks of Parkinson’s, dementia and Alzheimer’s
“The importance of inflammatory processes in Alzheimer’s disease (AD) has been confirmed during the past decade by the intensive investigation of inflammatory mediators in the brain of AD patients.” (Curr Alzheimer Res. 2011 Mar;8(2):132-410)
“There is a great deal of evidence suggesting an important role for systemic inflammation in the pathogenesis of Alzheimer’s disease.” (Neuropathol Appl Neurobiol. 2013 Feb;39(1):51-68)
“…converging evidence of a pathogenic role for activated microglia in Parkinsons’s has already begun to emerge.” (Int Rev Neurobiol. 2007;82:235-46)
Activated microglia discard the remnants of inflammasomes in tiny clumps called specks, and that these specks go on to seed new amyloid-β clusters, spreading the disease across the brain. This calls in more microglia…etc
Brain inflammation may be a cause of depression
One study found that patients with major depressive disorder had significantly higher levels of the pro-inflammatory cytokine TNF-alpha than their non-depressed counterparts. In addition, patients with depression had low levels of anti-inflammatory cytokines. (Curr Neuropharmacol. 2015;13(5):558-76)
Cytokines activate an enzyme that degrades serotonin resulting in low levels of the neurotransmitter. Decreased levels of the neurotransmitter serotonin are likely the contributing factor to the development of depressive symptoms.
In the brain, inflammation serves to shunt the use of tryptophan toward the production of anxiety-provoking chemicals, instead of toward serotonin and melatonin. Increased fatigue, sleep disturbance, decreased social activity, mobility, libido and decreased cognitive ability. Psychiatric researchers have observed that patients with higher levels of inflammatory markers (like CRP) are less likely to respond to antidepressants, and more likely to respond to anti-inflammatories.
A study involving depressed patients classified as non-responders supplemented the patients’ standard antidepressant treatment with the addition of aspirin, an anti-inflammatory. More than 50% of these patients responded to this combination treatment. At the end of the study, more than 80% of the group responsive to the anti-inflammatory went into remission.
“…reviews of the hundreds of papers published in this area have concluded that interleukin (IL)-6, tumor necrosis factor (TNFa) and C-reactive protein (CRP) are the most reliably elevated in patients with major depression.” (Depress Anxiety. 2013 Apr; 30(4): 297–306)
Brain inflammation in other disorders
Chronic Fatigue Syndrome
Characterized by profound fatigue that persists for more than six months. It is often accompanied by cognitive difficulties, muscle and joint pain, depression, poor sleep quality, or other nonspecific symptoms.
15 individuals who met diagnostic criteria for CFS were treated with the antiviral drug valacyclovir (Valtrex) and 93% of them exhibited a positive response, suggesting that viral infection, and possibly post-viral alterations in the host’s immune system.
Many individuals with CFS show signs of excessive inflammation and increased levels of the pro-inflammatory factors interleukin-1 and tumor necrosis factor-alpha (TNF-α). A 2014 brain imaging study found that individuals with CFS had significantly more neuroinflammation in many areas of the brain compared to healthy controls.
Fibromyalgia
Fibromyalgia is a condition of soft tissue pain, muscular stiffness, unremitting fatigue, disturbed sleep, and cognitive “slowing”, often associated with a variety of additional unexplained symptoms, psychological depression, and impairment of activities of daily living.
The serum of fibromyalgia patients commonly contains higher-than-normal levels of the pro-inflammatory cytokines interleukin-6 (IL-6).
Evidence of both neuro-inflammation (as assessed in cerebral spinal fluid) and chronic systemic inflammation.
Fibromyalgia subjects contained much higher levels of inflammation compared to healthy people. In particular, there were very high levels of certain chemicals secreted by neurons (brain and nerve cells) in response to injury.
Cancer and inflammation
Researchers are continuing to study links between inflammation and cancer. Studies suggest that inflammation promotes the initiation of cancer. There are studies on cancer stem cells maturation, metastasis, and links to decreased survival outcomes. When we look at peer-reviewed research, we find over ten thousand research reviews on human subjects over just a ten year period. That’s excluding clinical trials which would bring the total during that same period to more than thirty-four thousand. Next, lets look at some of the more notable studies and conclusions linking inflammation and cancer.
Inflammation promotes Cancer
“Inflammation is a recognized hallmark of cancer that substantially contributes to the development and progression of malignancies.” (Lancet Oncol. 2014 Oct;15(11):e493-503)
“Cytokines…activate the necessary pathways required by cancer stem cells to facilitate cancer stem cells progressing…and migrating to distant sites.” (Cancer Lett. 2014 Apr 10;345(2):271-8)
“Accumulating evidence shows that chronic inflammation can promote all stages of tumorigenesis, including DNA damage, limitless replication, apoptosis evasion, sustained angiogenesis, self-sufficiency in growth signaling, insensitivity to anti-growth signaling, and tissue invasion/metastasis.” (Oncology (Williston Park). 2011 Apr 30;25(5):400-10)
“Inflammatory conditions help to establish a microenvironment promoting cancer development, whereas a malignant tumor feeds the inflammatory response and accelerates tumor growth.” Crit Rev Oncog. 2009;15(1-2):43-63
NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis.
Inflammation and breast cancer
IL-6 has recently been shown to drive an inflammatory signaling pathway cascade that leads to more IL-6 production and breast cancer cell transformation and tumorigenesis (Rokavec et al., 2012). Breast cancer stem cells (CSC) represent a population of cells associated with treatment resistance and relapse following therapy (Kakarala and Wicha, 2008). IL-6 leads to expansion of breast CSC populations and resistance to trastuzumab in HER2+ breast cancer (Korkaya et al., 2012). These studies again suggest that IL-6 is one of the most important cytokines associated with breast cancer progression and treatment.
Chemotherapy strikingly induces endothelial cell production of TNF-α, which can promote breast cancer metastasis (Li et al., 2012). TNF-α induces expression of genes associated with invasion, proliferation, and metastasis in ERα+ breast cancer cells (Yin et al., 2009)
Inflammation also accelerates breast cancer progression by promoting tumor angiogenesis. (Leek et al., 1996; Lin et al., 2001; Lin and Pollard, 2007; Laoui et al., 2011)
“The balance between antitumor immunity (The strength of your immune system) and tumor-promoting inflammation determines whether the tumor will progress or be controlled or eliminated.”
“Inflammation-induced during the natural tumor progression is probably one of the main reasons that the immune system cannot effectively indefinitely restrain the expansion of breast cancer.”
“Moreover, inflammation induced during breast cancer therapy is often pro-tumorigenic and responsible for treatment resistance, and preliminary evidence suggests that it might also be involved in treatment-induced metastasis and relapse. Indeed, improved outcomes have been observed in patients receiving anti-inflammatory treatment in combination with standard breast cancer treatments.” (“The immune system and inflammation in breast cancer” Mol Cell Endocrinol. 2014 Jan 25; 382(1): 673–682)
Treating inflammation
Doctors treat inflammation with numerous drugs – targeting various cytokines with numerous occurrences of side effects.
TNFa blockers
Humira, Enbrel & Remicade
-
Common: Coughing, headaches, heartburn, nausea, vomiting,
stomach pain, weakness - Less common: colds, flu, urinary tract infections
- Rare: Lymphoma, skin cancer, serious brain reactions
IL6 blockers
Actemra, Kevzara
-
Common: Respiratory infections, headaches, high blood pressure,
liver injury, low WBC -
Less common: Tuberculosis, sepsis, fungal infections, shingles,
Thrombocytopenia - Rare: Cancer
IL1b blockers
Ilaris
- (only approved for rare auto-inflammatory diseases)
Natural ingredients studied to reduce inflammation
While FDA approved drugs are designed to target individual cytokines, there is abundant research to suggest that natural ingredients like curcumin have the ability to target a wide list of molecules from cytokines, enzymes, growth factors, receptors, proteins, and much more. Next, we’ll look at some of the most heavily-researched neutraceutical ingredients and functional foods related to the reduction of inflammation.
Curcumin
Curcumin, derived primarily from Turmeric roots has been the subject of thousands of studies and reviews. It has proved to be a remarkable subject for study with widespread applications far-reaching beyond inflammation reduction. Because its natural form faces challenges with bioavailability and absorption, supplement makers develop patented ways to increase its efficacy using methods like piperine (black pepper), fats/lipids, and essential oils.
Curcumin can reduce all of the inflammation-promoting molecular targets for which the FDA currently approves single-targeted (and often dangerous) pharmaceuticals. Some highlights from notable research:
By blocking the inflammatory master molecule nuclear factor-kappaB (or NF-kB), curcumin blunts cancer-causing inflammation, slashing levels of inflammatory cytokines throughout the body.
Curcumin has been shown in studies to reduce C-Reactive Protein by up to 50%!
Curcumin has been found to reduce cognitive dysfunction, neural synaptic damage, amyloid plaque deposition, and oxidative damage. It has also been found to modulate the levels of cytokines in brain neurons (Cole 2004; Mishra 2008).
“(Curcumin)…blocked activated microglial cell-mediated neuronal cell damage under inflammatory conditions. Indeed, curcumin blocked the production of pro-inflammatory and cytotoxic mediators such as…TNF-alpha, IL-1alpha, and IL-6 produced from…microglia.” (Pharmazie. 2007 Dec;62(12):937-42)
Curcumin downregulates the expression of the NF-κB –regulated gene products such as COX-2, TNF, 5-LOX, IL-1, IL-6, IL-8, MIP-1α, adhesion molecules, c-reactive protein (CRP), CXCR-4, and others. Curcumin also binds to COX-2 and 5-LOX and to inhibit their activity.
Hundreds of clinical studies now show Curcumin’s efficacy in Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, epilepsy, cerebral injury, CVDs, cancer, allergy, asthma, bronchitis, colitis, rheumatoid arthritis, renal ischemia, psoriasis, diabetes, obesity, depression, fatigue, and AIDS.
Boswellia
Unlike NSAIDs, Boswellia fights inflammation by blocking pro-inflammatory 5-LOX (5-lipoxygenase). 5-LOX is the first enzyme in the metabolic pathway leading to the synthesis of leukotrienes, which are harmful inflammatory substances that scientists believe may have a direct influence on a number of disease processes. Efforts to develop 5-LOX inhibitors that target asthma and cancer suggest that Boswellia extract may well have applications in managing these and other disease conditions.
Decreases the activity of another pro-inflammatory enzyme, HLE (human leukocyte elastase). HLE is associated with rheumatoid arthritis and respiratory illnesses such as pulmonary emphysema, cystic fibrosis, chronic bronchitis, and acute respiratory distress syndrome.
To date, the only anti-inflammatory compounds that have been found to inhibit both HLE and 5-LOX are those derived from Boswellia.
Boswellic acid also inhibits the production of pro-inflammatory cytokines, including TNF-α, IL-1, IL-2, IL-6, IL-12, and IFN-γ, by suppressing the activation of NF-κB.
Boswellia has shown successful studies in cancer, cardiovascular disease, inflammatory bowel disease, arthritis, asthma, and brain edema.
Additional anti-inflammatory herbs
In addition to Boswellia (an herbal extract also known as Indian frankincense), several herbs have been studied to target numerous pathways of inflammation – notably Stinging Nettle, Garlic, Celery, and Horsetail.
Stinging Nettle
“Our results suggest that part of the anti-inflammatory effect of Urtica extract may be ascribed to its inhibitory effect on NF-kappaB activation.” (FEBS Lett. 1999 Jan 8;442(1):89-94)
“After 8 weeks, IL-6 and hs-CRP showed a significant decrease in the intervention group (Stinging Nettle), compared
to the control group.” (Pak J Biol Sci. 2011 Aug 1;14(15):775-9)
Garlic
“Inhibition of nuclear factor-κB activation was the mechanism underlying this protective effect of garlic.” Molecules. 2014
Oct 31;19(11):17697-714
“Garlic resulted in a dose-dependent reduction of IL-6 and TNFalpha.” (Cytokine. 2015 Sep;75(1):117-26)
Celery
“Celery Seed has been found to be at least as effective as aspirin, ibuprofen, and naproxen in suppressing
arthritis…and reducing existing inflammation.” (Prog Drug Res. 2015;70:133-53)
“Celery Seed decreased the secretion of inflammatory cytokine TNF-α and IL-6 by 12-27%.” Am J Chin Med. 2015;43(3):443-55
Horsetail
“Significant down-regulatory effect on TNF-α and pre-inflammatory factor TNF-α.” (Pak J Pharm Sci. 2014 Nov;27:2019-23)
“Horsetail has an anti-inflammatory potential in the model of inflammation.” (Open Rheumatol J. 2013 Dec 30;7:129-33)
Talk to your doctor
Many of the conditions mentioned in this guide to inflammation are not self-diagnosable conditions. Talk to your doctor if you’ve got symptoms of these conditions or suspect chronic inflammation.
While many of our customers have been known to order their own lab tests (you can contract private laboratory testing to benchmark your levels for C-Reactive Protein, TNF Alpha, Interleukin 6, and more) elevated levels in these tests are not a substitute for a professional diagnosis.
Because the FDA doesn’t approve over-the-counter medications (only prescription drugs), we recommend researching both supplement ingredients and the companies that make them. Your doctor can help you decide if particular supplements are appropriate for you.
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