What are T Helper Cells 17 (Th17) and Interleukin-17?
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].
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 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].
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].
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].
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 periods of chronic stress can result in autoimmune issues.
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.
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.
Lifestyle to inhibit Th17
- Reduce stress [R]
- Sun/UV Exposure [R] and Nitric Oxide [R] – but not Th1.
- Exercise [R]
- Keeping a Circadian Rhythm [R]
- Cold Acclimation [R]
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
- Vitamin A/Retinol [R, R] (RAR alpha)
- Zinc [R], (STAT3-)
- Vitamin D3 [R], (via increasing C/EBP homologous protein)
- Potassium [R]
- Folate [R] – a deficiency causes a reduction of Treg cells in the small intestine.
- Chromium [R]
Hormones/NT’s to inhibit Th17
Supplements to Inhibit Th17/IL-17
- Probiotics: L. salivarius [R], L. plantarum [R]
- Curcumin [R]– IL23, IL17 [R]
- Berberine [R] (Clinical trial)
- EGCG [R]
- Ursolic acid [R] (potent)
- Andrographolide [R]
- Black Cumin Seed Oil
- Olive leaf extract [R, R],
- Fisetin [R] (inhibits IL-17)
- Chinese Skullcap/Baicalin [R, R] (Number of Th17 and IL-17)
- NAG [R],
- Red Yeast Rice/statins [R] – synergizes with corticosteroids
- Grape Seed Extract [R, R] (STAT3-)
- Boswellia [R]
- R-Lipoic Acid [R]
- Epimedium/Icariin [R]
- Apigenin [R]
- Honokiol [R]
- Aspirin [R]
- THC [R]
- CBD [R]
- Galantamine [R, R, R]
- Huperzine A [R]
- Nicotine [R, R, R]
- Butyrate [R]– but increases it in response to an infection [R]
- Cinnamon/NaB [R] (increases IL-17),
- Artemisinin [R]
- Beta-Caryophyllene [R]
- Resveratrol* [R, R] (conflicting),
- Probiotics: Enterococcus faecalis [R], (Mice)
- Parthenolide [R] – IL-17A [R]
- C60 [R]
- Ancient Wheat [R],
- Licorice/Lico A [R] – no increase in Tregs [R]
- Ginger extract [R]
Drugs That Inhibit Th17
Pathways to inhibit Th17
These actions inhibit Th17:
- CB2 Receptor activation [R]
- PPAR delta [R]
- PPARgamma [R]
- Vitamin D receptor [R]
- RAR alpha [R]
- LXR [R]
- DRD5 (-) [R]
- STAT3 (-) [R]
- STAT1 (-) [R]
- HDAC (-) [R]
- IDO (+) [R]
- DPP4 (-) [R]
- mTORC1 [R]
- Acetylcholinesterase (-) [R]
- Cyp11a1 (-)
- RORyt (-)
- HIF1a (+) [R]
- AKT(-) [R]
- Dopamine d1R(-)…, (inducible)……mTORC2(-) (natural)
- IL-1b (-) [R] – central role [R]
- IL-6 (-) [R] – central role [R]
- IL-23 (-) [R] – central role [R]
- TGF-b (-)
- H4R (-) [R]
- NF-kB (-) [R]
- GSK3 (-) [R]
- IL-17 (-) [R]
- IL-21 (-) [R]
- IL-10 (+)
- TNF (-) [R]
- IFN-b [R]
- IFNy [R]
- IL-12 [R]
- IL4 [R]
- PGE2 (-) [R]
- CD5 (-) [R]
Factors That Increase Th17 Immunity that You Should Avoid
- 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]
- 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]
- Klebsiella pneumoniae, Citrobacter rodentium, Candida albicans, Listeria monocytogenes, Salmonella enterica, Mycobacterium tuberculosis [R]
- Chlamydia [R]
- Certain gut microbes [R]
- Leptin [R] – leptin is elevated in obesity.
- Adiponectin [R] Increases Th1 and Th17 cells. This is elevated in thin people. This hormone is known for its insulin-sensitizing effects and is anti-cancer. However, it can be an indicator of the onset of some cardiovascular diseases and is highly present in inflamed tissues of patients with rheumatoid arthritis and inflammatory bowel disease.
- Aldosterone [R]. Aldosterone increases blood pressure. It’s usually associated with ill health. It promotes Th17 immunity.
- Insulin [R]
- IGF-1 [R]
- 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.
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.
mTOR Inhibitors Are Critical To Decreasing Th17 Cells
Increased mTOR promotes Th1 and Th17 immunity, leading to increased intestinal inflammation [R], among other issues.
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].