Inhibiting Interleukin-6 (IL-6): The Key To Health

Interleukin-6 (IL-6) is increased in almost all disease states. Read on to discover the causes of high IL-6 and natural hacks to decrease it.

What is Interleukin-6?

Interleukin-6 (IL-6) is a cytokine with well-defined pro- and anti-inflammatory properties [1]. It regulates the immune system and plays a role in cognitive function.

IL-6 is elevated when you are sick and after exercise, especially aerobic exercise [2].

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 [2]. 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 [3], so it’s worse for Th2 dominant folks. It also increases B cells, which is what produces antibodies and contributes to allergies and autoimmunity [4].

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 [5], chronic stress [6], too little sleep [7], eating too much – specifically, eating too much sugar or refined foods [8], smoking [9], excess alcohol, [10] and exercising too much [11] (more than 2 hours of intense exercise a day is probably not a good idea for most).

The Bad

IL-6 levels are increased in nearly all disease states [1].

It decreases Treg cells, which in turn blocks our ability to create tolerance for proteins we ingest – causing allergies [12]. It also increases the production of neutrophils, which is inflammatory [2].

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 [13].

IL-6 may cause feelings of “hopelessness“. This state strongly correlated with IL-6 levels [14] 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 [15].

IL-6 causes elevated blood sugar levels, which we know is problematic for general health [16].

IL-6 levels are higher in people with IBS [17, 18].

Studies have found that IL-6 aggravates the effects of stress hormones (CRH) on our gut mucosa, which causes IBS [19]. It also causes IBS by activating gut neurons [20], which alters peristalsis. IL-6 can cause leaky gut [21].

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) [22].

It increases nitric oxide [4], which can be good or bad, depending on the situation.

At higher levels, IL-6 increased the release of vasopressin and oxytocin [22], which acts to decrease urination, among other effects.

IL-6 suppresses or ‘hypermethylates‘ gene expression in the brain, which leads to a variety of problems [2].

For example, it decreases BDNF, a brain growth factor, which is how it contributes to depression [2].

People with major depressive disorder have elevated IL-6 (TNF-alpha) [23] and it likely contributes to a worse mood overall.

It can also lead to lower testosterone levels [24].

While IL-6 decreases testosterone in normal cells, it increases production in prostate cancer cells, which is required for this cancer to grow [25]. 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 [26, 27].

IL-6 contributes to schizophrenia by inhibiting (or hypermethylation) a gene (GAD67) that is important for GABA to work properly [2].

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 [28]. Resistant starch is a powerful way to inhibit HDAC and therefore increase BDNF.

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 [29]. Testosterone decreases these antibodies, but IL-6 is capable of increasing them even with high levels of testosterone [29]. (Estrogen increases these antibodies) [30].

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 [31]. IL-6 is elevated in people with tinea versicolor, a skin fungus [32]. IL-6 also increases Th22 cells, which disrupts skin microbial balance [33].

IL-6 (or IL-21 according to some) can increase Th17 cells, which are pro-inflammatory. To do this, you also need elevated TGF-β [34].

IL-6 can keep you from getting into ketosis [35].

The Good

I would say IL-6 is mostly bad if elevated, but brief spikes can be beneficial, just like brief bouts of intense exercise.

TNF and IL-1b increase IL-6 [36], but IL-6, in turn, suppresses both of these cytokines, which are more harmful than IL-6 itself. In this way, it’s an anti-inflammatory [37, 38].

IL-6 increases liver regeneration [39] and helps form emotional memories while sleeping [2].

IL-6 Makes Us Thinner

It also inhibits TNF, breaks down fat cells and decreases insulin resistance [40].

Science has discovered that exercise can help you lose weight more than by just burning calories; exercise changes your hypothalamus [41].

IL-6 is part of this mechanism by which exercise can help us lose weight [41].

IL-6 decreases insulin and leptin resistance in the hypothalamus, the gland that controls appetite (requires IL-10 to inhibit Nf-kB) [42].

IL-6 also increases spontaneous energy expenditure. Mice lacking IL-6 became obese [41].

IL-6 Can Fight Infections

IL-6 plays a protective role in many bacterial, viral, and fungal infections.

It has a protective role in the flu, H pylori, and EMCV [43]. Mice deficient in IL-6 are significantly more susceptible to some fungal infections like candida [44].

In mice, IL-6 helps prevent common herpes infection (HSV-1), but it doesn’t prevent its reactivation [45].

Diseases Associated With Interleukin-6

IL-6 is responsible for causing many autoimmune diseases [46]. 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) [2].

If you decrease IL-6, you will decrease the progression of many inflammatory conditions.

This is a partial list:

• Heart disease [47]
• Cancer (Myeloma [28], Prostate [28], Breast [48], etc…)
• Diabetes [28]
• Pain [49]
• Rheumatoid arthritis – strongest evidence [50], Fibromyalgia [51], Multiple Sclerosis [52], Behcet’s [53], SLE [54], System Sclerosis [46].
• Asthma. 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 [18], IBD, Crohn’s [46]
• Major depression [55], Bipolar [55], Schizophrenia [55], Alzheimer’s [28], Intellectual disability [56]
• Osteoporosis (postmenopausal) [57]. IL-6 promotes osteoclasts, which degrade bones [2].
• PCOS [58]
• Others: Diabetic neuropathy [59], Chemotherapy-induced neuropathy [60], Tinea versicolor, a skin fungus [32], Carpal Tunnel Syndrome [61], Polymyalgia Rheumatica [62].

Top Ways to Inhibit IL-6

• Spices: Bay leaves [63], Black pepper [63], Nutmeg [63], Oregano [63], Sage [63]
• Jo’s Resistant starch [64]
• Zinc [65]
• Magnesium [66]
• Probiotics: B. infantis [67], S. boulardii [68], L. casei [69], L. Salivarius [70]
• Trehalose [71, 72]
• Jasmine Tea/EGCG[73]
• Vitamin D3 [74]
• PQQ [75]
• Andrographis/Andrographolide [76] – 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 [77]
• Curcumin [78, 79]
• Licorice [80]
• Fish oil/DHA [81]
• Fisetin [82]
• Cinnamon [63] /Sodium Benzoate
• Molecular hydrogen machine [83]
• Aspirin [84]
• Boswellia [85]
• Lithium [86]
• Hydroxytyrosol [87]
• Apigenin [63]
• Luteolin [88]
• Quercetin [63]
• Resveratrol (500 mg, with 5 g leucine) [79, 89]
• Red Yeast Rice/Lovastatin [90]

Factors That Increase Interleukin-6 Levels

Interleukin-6 Inhibitors

Lifestyle/Diet

• Positive emotions were associated with lower IL-6 (especially awe, wonder, and amazement) [118].
• Calorie Restriction [119]
• Wim Hof Breathing/Meditation [120]
• Napping after sleep loss [121]
• Vegetables/Phytosterols [122]
• LLLT [123, 124, 125]
• Legumes [126]
• Nuts [127]
• Oat polyphenols [128]
• Mediterranean diet [129]
• Olive oil [130]
• Ancient wheat [131]
• Fish oil [132]
• Phytic acid [133]
• Blueberry [134]
• Music [135]
• Honey [136]
• Elemental diet in Crohn’s disease [137]
• Broccoli sprouts/Sulforaphane [138]
• Soy [139]
• Oats [140]
• Cashew [96]
• Spirulina [141]
• Stevia [142, 143]
• Garlic [144] (raw is better)
• Red raspberries [145]
• Jasmine Tea [146]

Nutrients

• Vitamin B-12 [92]
• Fish oil [147, 148]
• Magnesium [149]
• Chromium [150]
• Arginine [151]
• Histidine [152]
• Vitamin E [153] – rats fed oxidized oils.

Hormones

• MSH [154]
• ACTH [154]
• Vitamin D3 [74]
• Progesterone [155]
• Testosterone [29]
• Ghrelin [156]

Supplements

• Bile [157]
• Glycine [158]
• Inositol [159]
• Bromelain [160]
• Ginkgo [161]
• Sialic Acid [162, 163]
• Berberine [164]
• Elm bark [165]
• Apple polyphenols [166]
• Chinese Skullcap [167]
• Carnosine [168]
• LDN [169]
• Grape Seed Extract [170]
• Betulin/Chaga [171]
• Cocaine [172]
• Honokiol [173]
• Artemisinin [174]
• Baicalin [175]
• RLA (Lipoic Acid) [176]
• Lactoferrin [177]
• Mastic gum [178]
• Ashwagandha
• Alfalfa – potent [179]
• Caffeic acid (Chlorogenic acid has caffeic acid) [180]
• Ellagic acid [180]
• Fucoidan [181]
• Astaxanthin [182]
• Astragalus [183]
• Danshen [184]
• Dandelion [185]
• Genistein [186]
• Hesperidin [187]
• Tart Cherry [188]
• Vitamin E/Tocotrienols [189]
• Antler velvet [190]
• Quercetin [82]
• Rutin [82]
• Myricetin [82]
• Echinacea [191]
• Rosmarinic acid [192]
• Red clover [193]
• Bitter melon [194]
• Magnolol [195]
• Glutamine [196]
• Allegra/Fexofenadine [197]
• Metformin [198]
• MSM
• Chrysin [199]
• Electroacupuncture [200], Structured water [201], Mizolastine (antihistamine) [197], Oxymatrine [202], Methotrexate (drug) [203], Sumac [204], Perilla [205], Tibetan medicated-bath [206].

Mechanisms

• ACE inhibitors [105]
• PPARy
• STAT3 inhibitors [207]

Interleukin 6 on SelfDecode

• Interleukin 6 measurement SNPs
• Interleukin 6 search

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 [208]. Depressed people had IL-6 levels about 1.78 pg/ml greater than healthy people [209].

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 [50]. (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 [210]. (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” [210]. 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) [211]. 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 [212]. 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 [213]. 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) [213, 214]. The average IL-6 level for people with bacterial infections was 237 pg/ml. It was undetectable for viral infections [215].

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 [50].

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.

CRP is produced by the liver AND fat cells [216], so it makes sense that it’s more elevated in overweight people [217].

CRP is mainly increased by IL-6 [218], but also IL-1b and TNF.

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.

To illustrate my point, many studies show IL-6 is elevated with IBS [17, 18]. However, when a study checked for hs-CRP and IBS, the differences were significant but very small.

People with IBS have an average hs-CRP of 1.17, while healthy controls have a level of 0.72 [219]. 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 [212].

Another example is cognitive decline. According to a study, elevated IL-6 but not CRP in midlife predicts cognitive decline [13]. Obviously, these two inflammatory markers aren’t two peas in a pod.

In another example, although CRP levels were significantly lower in SLE than in Rheumatoid Arthritis, the concentrations of circulating TNF-alpha were higher in SLE [54].

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.