What is Interleukin-6?
If exercise increases inflammatory markers, then why is exercise healthy? Well, when you exercise, your muscles release IL-6, which is anti-inflammatory. However, when your immune cells (macrophages) release it, it’s pro-inflammatory (R). The harmful effect has to do, in part, with it being released with other immune cells that synergize in a negative way.
IL-6 also suppresses Th1 cells, while it induces Th2 cells (R), so it’s worse for Th2 dominant folks. It also increases B cells, which is what produces antibodies and contributes to allergies and autoimmunity (R).
People who aren’t predisposed to autoimmune issues can also have elevated IL-6. It’s the cytokine that is involved in the diseases of modern civilization. The most common cause is probably obesity.
There are two ways that IL-6 can activate cells. One way is anti-inflammatory and helps in tissue regeneration. Another is pro-inflammatory and causes all kinds of problems. See below for a more detailed explanation.
The most common reasons for elevated IL-6 are obesity (R), chronic stress (R), too little sleep (R), eating too much – specifically, eating too much sugar or refined foods (R), smoking (R), excess alcohol, (R) and exercising too much (R) (more than 2 hours of intense exercise a day is probably not a good idea for most).
IL-6 levels are increased in nearly all disease states (R).
It decreases Treg cells, which in turn blocks our ability to create tolerance for proteins we ingest – causing allergies (R). It also increases the production of neutrophils, which is inflammatory (R).
Interleukin-6 is a decent predictor of cognitive decline in late midlife. A 10-year decline in reasoning was greater among people with high IL-6 than those with low IL-6. In addition, people with high IL-6 had 1.81 times greater odds of a decline in a test that measures normal cognitive function (R).
IL-6 may cause feelings of “hopelessness”. This state strongly correlated with IL-6 levels (R) and we know this cytokine can cause brain changes that lead to a worsened mood. IL-6 is also correlated with violent suicide, impulsivity, and monotony avoidance (R).
IL-6 causes elevated blood sugar levels, which we know is problematic for general health (R).
Studies have found that IL-6 aggravates the effects of stress hormones (CRH) on our gut mucosa, which causes IBS (R). It also causes IBS by activating gut neurons (R), which alters peristalsis. IL-6 can cause leaky gut (R).
IL-6 may lessen fatigue by stimulating the HPA axis and suppressing TNF-alpha (thereby increasing orexin). Specifically, it stimulates the release of the corticotrophin-releasing hormone (CRH) by the hypothalamus (reversed by a COX inhibitor) (R).
It increases nitric oxide (R), which can be good or bad, depending on the situation.
IL-6 suppresses or ‘hypermethylates’ gene expression in the brain, which leads to a variety of problems (R).
While IL-6 decreases testosterone in normal cells, it increases production in prostate cancer cells, which is required for this cancer to grow (R). So it’s a double whammy – it decreases testosterone in normal cells and increases it in cancer cells. Damn you, IL-6!
IL-6 also decreases performance by decreasing the conversion of T4 to T3 (thyroid hormones), resulting in lower levels of T3. This occurs as a result of IL-6 causing oxidative stress and lowering glutathione levels (R, R2).
HDAC inhibitors are beneficial for cognitive disorders because they increase gene expression for growth factors like BDNF. IL-6 does the opposite by increasing HDAC (R). Resistant starch is a powerful way to inhibit HDAC and therefore increase BDNF (R).
IL-6 is the most potent inducer of CRP, an inflammatory marker, but as I will explain below, you can have normal CRP levels and abnormal IL-6 levels.
It can create and worsen food sensitivities and autoimmune issues by increasing IgG and IgM antibodies (R). Testosterone decreases these antibodies, but IL-6 is capable of increasing them even with high levels of testosterone (R). (Estrogen increases these antibodies) (R).
IL-6 can also cause skin problems. When your natural skin fungus gets out of control the body attacks it with cytokines that include IL-6 (also IL-1b, TNF, IL-8), which recruits other aspects of the immune system (R). IL-6 is elevated in people with tinea versicolor, a skin fungus (R). IL-6 also increases Th22 cells, which disrupts skin microbial balance (R).
I would say IL-6 is mostly bad if elevated, but brief spikes can be beneficial, just like brief bouts of intense exercise.
IL-6 Makes Us Thinner
IL-6 is part of this mechanism by which exercise can help us lose weight (R).
IL-6 also increases spontaneous energy expenditure. Mice lacking IL-6 became obese. (R)
IL-6 Can Fight Infections
IL-6 plays a protective role in many bacterial, viral, and fungal infections.
In mice, IL-6 helps prevent common herpes infection (HSV-1), but it doesn’t prevent its reactivation (R).
Diseases Associated With Interleukin-6
IL-6 is responsible for causing many autoimmune diseases (R). There are many theories about how this occurs, but the point is that it’s causal and not just correlated. One way IL-6 does this is by decreasing the cells that regulate the immune system from attacking itself (Treg cells) (R).
If you decrease IL-6, you will decrease the progression of many inflammatory conditions.
This is a partial list:
- Heart disease (R)
- Cancer (Myeloma (R), Prostate(R), Breast (R), etc…)
- Diabetes (R)
- Pain (R)
- Rheumatoid arthritis – strongest evidence (R), Fibromyalgia (R), Multiple Sclerosis(R), Behcet’s (R), SLE (R), System Sclerosis (R).
- Asthma (R). IL-6 promotes Th2 activation and allergic responses and inhibits the activity of regulatory T cells (Tregs), which helps get rid of substances you’re allergic to.
- IBS (R), IBD (R), Crohn’s (R)
- Major depression (R), Bipolar (R), Schizophrenia (R), Alzheimer’s (R), Intellectual disability (R)
- Osteoporosis (postmenopausal) (R). IL-6 promotes osteoclasts, which degrade bones (R).
- PCOS (R)
- Others: Diabetic neuropathy (R), Chemotherapy-induced neuropathy (R), Tinea versicolor, a skin fungus (R), Carpal Tunnel Syndrome (R), Polymyalgia Rheumatica (R).
Top Ways to Inhibit IL-6
- Spices: Bay leaves (R), Black pepper (R), Nutmeg (R), Oregano (R), Sage (R)
- Resistant starch (R)
- Zinc (R)
- Magnesium (R)
- Probiotics: B. infantis (R), S. boulardii (R), L. casei (R), L. Salivarius (R)
- Trehalose (R, R)
- Jasmine Tea/EGCG (R)
- Vitamin D3 (R)
- PQQ (R)
- Andrographis/Andrographolide (R) – Out of 20 plants tested, Andrographis inhibited IL-6 the most and was more potent than dexamethasone. (IC50= .74mcg/ml)
- Black Cumin Seed Oil /Thymoquinone (R)
- Curcumin (R, R)
- Licorice (R)
- Fish oil/DHA (R)
- Fisetin (R)
- Cinnamon (R) /Sodium Benzoate
- Molecular hydrogen machine (R)
- Aspirin (R)
- Boswellia (R)
- Lithium (R)
- Hydroxytyrosol (R)
- Apigenin (R)
- Luteolin (R)
- Quercetin (R)
- Resveratrol (500mg, with 5g leucine) (R, R)
- Red Yeast Rice/Lovastatin (R)
Factors That Increase Interleukin-6
- High blood sugar levels – High blood sugar levels activate immune cells like monocytes and increase inflammation (R).
- PHA (lectin) (R), ConA (lectin) (R)
- High glycemic index foods (R)
- High-fat diet (R)
- Coffee (R) – People who drank more than a cup had 50% greater IL-6 (association). Seems to be confirmed in a randomized control trial in people with diabetes, which showed a similar 60% increase (R).
- Acrylamide (R) – found in starchy foods such as potato chips (potato crisps), French fries, and bread that had been heated higher than 120°C (248°F) (production of acrylamide in the heating process was shown to be temperature-dependent). It was not found in food that had been boiled. Acrylamide is also found in black olives, prunes, dried pears, coffee, cocoa powder, and chocolate, formed during cacao bean roasting (R).
- Chronic insomnia (R) – Elevates IL-6 in the day time.
- Sleep deprivation (R)
- Excessive exercise/Marathons (R)
- Obesity (R)
- Circadian Rhythm disruption (R)
- Smoking (R)
- Excess alcohol (R)
- Chronic stress (R)
- Viruses, like Herpes Virus (HHV8), can produce a protein similar to IL-6 that is even more inflammatory (R).
- Infections (some). For example, people with lingering symptoms from Lyme have elevated IL-6 (R).
- Vitamin D deficiency (R)
- Zinc deficiency (R)
- Magnesium deficiency (R)
- Calcium deficiency (R)
- Vitamin C deficiency (R)
- Choline Deficiency (R) – People who consumed more than 310 mg per day had a 26% lower concentrations of IL-6 than those who consumed less.
- Aloe (R) – (in cancer cells)
- 5-HTP (at lower and higher concentrations) (R)
- Reishi (R)
- Grapeseed extract (R) – in astrocytes, which is neuroprotective.
- Astragalus (R)
- Cat’s Claw (R)
- Rooibos (R)
- Grape powder (R) (LPS)
- Creatine at very high dosages (R)
- Phosphatidyl Choline— in response to infection (R)
- Antidepressants: Imipramine and venlafaxine (at the higher concentration) (R). A combination of 5-HTP and fluoxetine (antidepressants) (both at the lower concentration) (R).
- Positive emotions were associated with lower IL-6 (especially awe, wonder, and amazement) (R).
- Calorie Restriction (R)
- Wim Hof Breathing/Meditation (R)
- Napping after sleep loss (R)
- Vegetables/Phytosterols (R)
- LLLT (R, R, R)
- Legumes (R)
- Nuts (R)
- Oat polyphenols (R)
- Mediterranean diet (R)
- Olive oil (R)
- Ancient wheat (R)
- Fish oil (R)
- Phytic acid (R)
- Blueberry (R)
- Music (R)
- Honey (R)
- Elemental diet in Crohn’s disease (R)
- Broccoli sprouts/Sulforaphane (R)
- Soy (R)
- Oats (R)
- Cashew (R)
- Spirulina (R)
- Stevia (R, R)
- Garlic (R) (raw is better)
- Red raspberries (R)
- Jasmine Tea (R)
- Vitamin B-12 (R)
- Fish oil (R, R)
- Magnesium (R)
- Chromium (R)
- Arginine (R)
- Histidine (R)
- Vitamin E (R) – rats fed oxidized oils.
- Bile (R)
- Glycine (R)
- Inositol (R)
- Bromelain (R)
- Ginkgo (R)
- Sialic Acid (R, R)
- Elm bark (R)
- Apple polyphenols (R)
- Chinese Skullcap (R)
- Carnosine (R)
- LDN (R)
- Grape Seed Extract (R)
- Betulin/Chaga (R)
- Cocaine (R)
- Honokiol (R)
- Artemisinin (R)
- Baicalin (R)
- RLA (Lipoic Acid) (R)
- Lactoferrin (R)
- Mastic gum (R)
- Ashwagandha (R)
- Alfalfa – potent (R)
- Caffeic acid (Chlorogenic acid has caffeic acid) (R)
- Ellagic acid (R)
- Fucoidan (R)
- Astaxanthin (R)
- Astragalus (R)
- Danshen (R)
- Dandelion (R)
- Genistein (R)
- Hesperidin (R)
- Tart Cherry (R)
- Vitamin E/Tocotrienols (R)
- Antler velvet (R)
- Quercetin (R)
- Rutin (R)
- Myricetin (R)
- Echinacea (R)
- Rosmarinic acid (R)
- Red clover (R)
- Magnolol (R)
- Glutamine (R)
- Allegra/Fexofenadine (R)
- Metformin (R)
- MSM (R)
- Chrysin (R)
- Electroacupuncture (R), Structured water (R), Mizolastine (antihistamine) (R), Oxymatrine (R), Methotrexate (drug) (R), Sumac (R), Perilla (R), Tibetan medicated-bath (R).
Interleukin 6 on SelfDecode
What Are Healthy Interleukin-6 Blood Levels?
In healthy subjects, IL-6 blood levels are barely detectable and range between 2-6 pg/ml. Another study mentions that healthy people have a median level of 0.5 pg/ml (R). Depressed people had IL-6 levels about 1.78pg/ml greater than healthy people (R).
In people with Rheumatoid Arthritis, levels can increase up to a thousand-fold (not common). In sepsis, which is extremely dangerous, it can increase up to a million-fold (R). (Sepsis is a potentially fatal whole-body inflammation caused by severe infection).
Chronically elevated levels will cause harm in the long run. One study checked for diseases of aging and IL-6 levels. After adjustment for potential confounders, they found that having a high interleukin-6 level (greater than 2.0 pg/ml) twice over a 5-year period nearly halved the odds of “successful aging” at the 10-year follow-up and increased the risk of future heart disease and overall death (R). (They only checked IL-6 levels twice).
Note that all of the people in the study were free of cancer and heart disease, so these weren’t what you’d call really sick people. They defined successful aging as “being free of major chronic disease and with optimal physical, mental, and cognitive functioning” (R). I couldn’t define it better myself.
In people who exercised for 3-3.5 hours (marathon exercise), IL-6 increased from 1.5 pg/ml to 94.4 pg/ml immediately post-exercise and to 22.1 pg/ml 2 hours post-exercise (half-life of 1-2 hours) (R, R2). This means blood levels should be completely normal the next day – even after running a marathon.
In a group of people with cirrhosis, everyone with a proven bacterial infection had IL-6 levels above 200 pg/ml. On the other hand, 74% of the people with high IL-6 levels had these bacterial infections (R). These people had cirrhosis, so it would make sense that many would have high inflammation without bacterial infections. The takeaway is if you have high IL-6 levels without a chronic inflammatory condition, I would suspect some kind of infection.
In another study, patients hospitalized for moderate bacterial and viral infectious diseases were checked for their cytokines. IL-6 was associated with a bacterial rather than a viral infection (R). This is useful information when trying to figure out if someone’s problems are more likely viral or bacterial. In the study, people who took antibiotics had their IL-6 normalize after only 3 days (from 39 to 2) (R, R). The average IL-6 level for people with bacterial infections was 237 pg/ml. It was undetectable for viral infections (R).
I had a client check her IL-6 levels and her result was 528 pg/ml. This client had high IL-6 at 528 pg/ml and her hs-CRP was 0.4, which is very low. Therefore, IL-6 is the main driver CRP, but CRP is not a reliable indicator, as you’ll read below.
It should be noted that these numbers do not take into account the local IL-6 levels at the site of inflammation, which is largely unknown since they are mostly not experimentally accessible (R).
This can be the case where inflammation is more localized, so it won’t be picked up by these tests. Therefore, not having elevated inflammatory cytokines isn’t definitive, but if you do have elevated cytokines, it’s certainly telling.
CRP Isn’t Such A Reliable Factor
The most common way of checking inflammation – high-sensitivity C-reactive protein (hs-CRP) is not very relevant.
IL-6 will be elevated moderately if you are overweight since IL-6 is also secreted by fat cells.
CRP will only show a spike, however, if you run marathons (maybe), have an acute infection, or incur a serious injury. These are situations where IL-6 spikes.
However, in most people with chronic inflammation who are thin, CRP will likely come back normal.
My CRP levels were low even when I was experiencing chronic, low-grade inflammation, and I didn’t experience fever.
People with IBS have an average hs-CRP of 1.17, while healthy controls have a level of 0.72 (R). The standard value is under 3.0.
No doctor would even blink at the difference between 1.17 and 0.72. They would tell you that you are perfectly healthy.
C-reactive protein correlated only weakly with interleukin-6 levels in people with cirrhosis (R).
Another example is cognitive decline. According to a study, elevated IL-6 but not CRP in midlife predicts cognitive decline (R). Obviously, these two inflammatory markers aren’t two peas in a pod.
I had a client with highly elevated IL-6 but at the same time a very low hs-CRP (0.4).
So we see from the IBS example that hs-CRP can tell us something, but we also see that in conditions with elevated IL-6, CRP can be more or less normal.
This is why we shouldn’t rely on hs-CRP as an indicator of inflammation and should take other tests.
IL-6: Pro and Anti-Inflammatory Effects
There are two types of IL-6. One is called “Classic signaling” and the other is called “Trans-signaling.”
IL-6 Classic signaling is needed for regenerative and anti-inflammatory roles.
IL-6 Trans-signaling takes place when IL-6 receptors (soluble IL-6 receptors or sIL-6R) in the blood bind with IL-6. This kind of cellular activation by IL-6 is what causes inflammatory problems (R).
In models of inflammation, autoimmune diseases, and inflammation-associated cancer, blockade of IL-6 trans-signaling was sufficient to block the inflammatory progress (R).