What are T Helper Cells 17 (Th17) and Interleukin-17?

T helper cells start off ‘naive’ T cells and can turn into  Th1, Th2 or Th17 cells.

A naive T cell can either become an inflammatory Th17 cell or anti-inflammatory Treg cells.  The goal for people with Th17 inflammation is to convert more of these cells to Treg cells.

Technical: Cytokines or the lack of them influence which cell the naive helper cell will convert into. The two necessary cytokines are TGFb and IL-6, which I’ve spoken about.  IL-6 (some say IL-21) is what ultimately determines if it turns into an inflammatory or anti-inflammatory cell.   IL-23 is a cytokine that determines if these Th17 will cause disease [R].  IL-1β can also increase the production of Th17 cells [R].

Th17 cells produce the cytokine IL-17, as well as TNF  and others [R].

IL-17 increases kynurenine (so does cortisol, IL-1, TNF and IFNy/Th1 dominance) [R].  This was found to be elevated in IBS [R]. Overall, increasing this pathway probably isn’t a good idea, although the effects are mixed [R].  It increases oxidative stress and leads to depression.

Kynurenine can then turn into kynurenic acid or quinolinic acid.  Kynurenic acid blocks NMDA, AMPA, glutamate and nicotinic receptors, all of which are important for learning and memory.  Thus, Kynurenic acid can make us dumber [R]. Inhibiting Kynurenic acid can result in cognitive enhancement [R].

548086.fig.001

Interleukin 17 acts synergistically with TNF and IL-1 [R]. (Not a word, but it should be. It means the opposite of synergistically.)

IL-17 is commonly associated with allergic responses. IL-17 induces the production of many other aspects of inflammation such as IL-6, IL-1β, TGF-β, TNF, IL-8, MCP-1, and PGE2) from many cell types. The release of cytokines causes many negative events such as airway narrowing in people with asthma (by fibrosis) [R].

Th17 cells have a circadian rhythm.   The amount of Th17 cells changes during the day-night cycle.  The production of Th17 is higher at midnight than at noon [R].

Th17 and IL-17 aren’t bad in all ways.  Th17 has a protective role in combating fungi [R] and some bacterial infections (‘extracellular’) [R].  Tregs also help combat bacteria [R].   Increased Th17 may also be anticancer in some ways [R].  There are well-known cancer and autoimmune trade-off spoken about in the literature.

Researchers also found that in people with food allergies (classical type), IL-17 production was impaired, but not in healthy people.  The study found IL-17 was a potential biomarker for tolerance to food antigens [R].

Normal IL-17A levels are 0.89 pg/ml.  In people with mild sleep, apnea levels are 1.02 pg/ml, in moderate sleep apnea 1.18 pg/ml, and in severe sleep apnea 1.62 pg/ml. (all median values) [R].

Th17 cells appear to be resistant to the suppressive effects of Tregs [R, R].

Males vs Females

Women are also more susceptible than men to develop a host of autoimmune conditions, including Multiple Sclerosis (female to male ratio of 2:1), Rheumatoid Arthritis (2:1), Systemic Lupus Erythematosus (9:1), Sjogren’s syndrome (9:1), and Hashimoto’s thyroiditis (9:1) [R].

The higher female prevalence of these diseases may be related to the fact that women develop more robust immune responses than men [R].

Women have higher levels of Th1 cells, IgM, and CD4+ cell counts, and show stronger immune response responses to vaccinations [R].

Females are more prone to Th1 dominance, while males are more prone to Th17 dominance [R].

This is because Androgens increase PPAR alpha, which causes inhibition of Th1 dominance.  At the same time, men have lower PPAR gamma, which leads to Th17 dominance [R].

To some extent, Th1 and Th17 ‘compete’ with each other.  IL-2 produced by Th1 cells activates STAT5, which competes with STAT3 (which produces Th17 dominance) [R].

Supporting this, castration of male mice enhances Th1 autoimmunity and lowers Th2 cytokine production [R].

Diseases Associated With Increased Th17

  • Several Autoimmune diseases: Hashimoto’s [R], Grave’s [R], Multiple Sclerosis [R], Lupus/SLE [R], Uveitis [R], Type 1 diabetes [R], Systemic Sclerosis [R], Autoimmune myocarditis [R], Vitiligo [R]
  • Heart disease [R, R] (IL-17) – contradictory [R]
  • IBS [R]– some cases
  • Rheumatoid arthritis [R, R]
  • Hashimoto’s [R], Graves [R]
  • Multiple Sclerosis [R],
  • Asthma [R], Airway inflammation [R]
  • IBD [R]: Crohn‘s [R], Colitis [R]
  • Sleep apnea [R] One study claims that Th17 causes sleep apnea [R]
  • Skin: Acne Lesions [R], Psoriasis [R, R], Eczema [R]
  • Some cancers: Leukemia [R], Multiple Myeloma
  • Fibromyalgia [R] – increased IL-17A
  • Osteoporosis [R, R] – Women in menopause have less
  • Depression [R] – IL17 and TGFbeta1 are higher in depressed patients [R].
  • Infertility in women. Having an elevated Th17 immune system can cause infertility by attacking sperm. Estradiol (E2) inhibits Th17 cell responses. The reason this occurs is so that sperm is not attacked during estrus.  This explains the connection between fungal infections, which increases Th17 immunity, and female infertility  [R].
  • Periodontal Disease [R].
  • Chronic Lyme’. Lyme or B burgdorferi is able to increase IL-6, IL-1b, IL-23, and TGFb.  This increases Th17 immunity and could cause Lyme arthritis [R].
  • Stroke damage – some of the damage after strokes may be caused by IL-17 [R].

Th17 is lower in chronic fatigue syndrome [R], but I don’t see how this contributes to it.

Studies in animal models of MS suggest that Th1 cells are important in initiating acute attacks, while Th17 cells are more important in mediating progression of this disease. Consistent with this, IL-17 is expressed at higher levels in chronic versus acute MS lesions [R].

Why Some People Do Worse With Higher Protein, Kombucha

Th17 can explain why a bout of chronic stress can result in autoimmune issues.

Th17 can also partly explain why some do worse with a higher protein diet when they’re inflamed.  This is because Tryptophan, and Arginine to a lesser extent, can increase Th17.

Other amino acids can activate mTOR, which increases Th17 immunity.

Kombucha decreases Th17 cells but can increase IL17 release, which is just as bad as increasing Th17, because the negative effects are mediated through the cytokines.

Circadian disruptions increase Th17 cells, while tanning in the sun strongly inhibits this response.  This could help explain why people who live further from the equator are more likely to get autoimmune diseases.

Also, paleo diets have more Zinc, Vitamin A and D3, which can help reduce Th17 immunity.

How to Inhibit Th17 and IL-17 

Usually, substances that inhibit Th1 cells also inhibit Th17 cells.  There are some exceptions.

IL-17 is one of the main cytokine released by Th17 cells, so inhibiting this cytokine blocks most or all of the damage caused by these cells.

There are two proteins that allow the cytokine IL-17 to be produced: STAT3 and Nf-kB [R].  I wrote how to inhibit Nf-kB and I describe below how to inhibit STAT3.

Lithium only inhibits Th1 but not Th17 [R].

Lifestyle to inhibit Th17

Diet to inhibit Th17

  • Avoid lectins* [R]
  • Fish oil [R] (reduced the surface expression of both IL-6R and IL-23R)
  • Broccoli sprouts/Sulforaphane [R],
  • One meal per day (in response to LPS) [R]
  • Coffee [R]
  • Kombucha/Lactic acid [R] –  although it increases IL-17A, the cytokine released by this cell.

Nutrients to inhibit Th17

Hormones/NT’s to inhibit Th17

Supplements to Inhibit Th17/IL-17

Drugs That Inhibit Th17

Pathways to inhibit Th17

These actions inhibit Th17:

Factors That Increase Th17 Immunity that You Should Avoid

Lifestyle

  • Chronic psychological stress/anxiety.  In a sentence, chronic stress causes cortisol/glucocorticoid ‘resistance’ [R].  The implications are that your autoimmune/inflammatory issues will worsen before you start to improve when you reduce stress.  This means that a higher level of cortisol is needed to suppress the immune system.  Stress causes epinephrine to be released and helps cause a dominant Th2/Th17 profile. Therefore, stress can affect inflammatory conditions by favoring Th17 immunity. [R]  Cell cultures from anxious individuals showed Th17 dominance.  These people produced higher amounts of IL-17 and TNF.   In healthy people, glucocorticoids/cortisol decreased excessive Th17 activation, but not in highly stressed people. The anxious people became insensitive to glucocorticoids [R]. Also, adrenaline, which is a Beta2-AR agonist, aggravates IL-17-type immune response [R].  Asthma drugs also worsen this response and these drugs are associated with disease progression (but they offer temporary relief).
  • Marathons/Excess exercise [R].  I caution against excessive exercise in general.
  • Obesity [R]
  • Circadian Rhythm disruption [R],
  • EMFs [R]

Diet

  • Gluten [R],
  • Cholesterol (desmosterol) [R] (not necessarily influenced by dietary cholesterol)
  • Iodine excess [R] – moderate to high.  Extremely high levels result in Th1 elevation [R].  There’s a fad in the alternative health community to take excessive iodine.  I don’t agree with this approach, even if some people claim it helped them.  Make sure you aren’t Th1 dominant.   I take about 400mcg of supplemental iodine a day and recommend this to most people.
  • Tryptophan (by deactivating IDO) [R, R]
  • Arginine [R]
  • Frying oils/Smoking (both produce oxysterols) [R]. Also, the enzyme CYP27A1 turns cholesterol into bile and this enzyme can increase oxysterols and therefore Th17 dominance [R].
  • High salt diet [R] – there’s a high salt fad in the alternative health community.  Just make sure you’re not Th17 dominant before you start going crazy with salt.
  • Long chain fatty acids [R]

Toxins/Infections

  • Free radicals [R]
  • Fungal infections [R]
  • Viruses
  • Intracellular and extracellular bacteria [R]
  • Parasites [R]
  • Heavy Metals: Cadmium, Mercury and probably Lead and Arsenic [R]
  • Flu Viruses [R]
  • Klebsiella pneumoniae, Citrobacter rodentium, Candida albicans, Listeria monocytogenes, Salmonella entericaMycobacterium tuberculosis [R]
  • Chlamydia [R]
  • Certain gut microbes [R]

Hormones

Supplements

  • Forskolin [R]
  • Uric acid (in combination with IL1b and IL18) [R]
  • Resveratrol [R] – contradictory
  • NAD+/Niagen NAD. Although it increases both Th1 and Th17 cells, it decreases their ability to cause disease [R]
  • Butyrate [R] – in response to LPS.  However, it increases Tregs [R].
  • L Casei [R], S Boulardii [R], Bacillus Subtilis [R]– increases IL-17.

Pathways

Genes and Th17

These genes are associated with Th17 immunity.

STAT3 Inhibitors Are Critical To Decreasing Th17 Cells

STAT3 is a protein that binds to DNA and increases gene expression.

STAT3 is essential for the production of the TH17 cells, so if you reduce this protein, Th17 cells inevitably decline [R].

Unsurprisingly, STAT3 plays an important role in autoimmune and inflammatory diseases and some cancers.

See more about STAT3 and a list of natural inhibitors.

mTOR  Inhibitors Are Critical To Decreasing Th17 Cells

Increased mTOR promotes Th1 and Th17 immunity, leading to increased intestinal inflammation [R], among other issues.

mTOR increases another protein called hypoxia-induced factor (HIF)-1α, which increases Th17 cells [R]

Inhibiting mTOR is a significant pathway to decrease Th1 Cells.

This is a good picture that shows you the conditions needed for these four T Cells.

Technical: mTOR increases glycolysis, which is what allows Th17 cells to proliferate. This works through HIF1α. Blocking glycolysis inhibited Th17 development while promoting Treg cell generation [R].

Read this post on how to inhibit mTOR.

Images

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