Th17 cells produce inflammatory cytokines like IL-17 and TNF-alpha. As part of a series on immune health, this post goes over the Th17 response, associated diseases, and complementary approaches — including lifestyle, food, and supplement choices — that may help keep the immune system in good health.
What are T Helper Cells 17 (Th17) and Interleukin-17?
Reconciling Th1/Th2 Discrepancies
You’ve probably heard about the Th1 and Th2 response. To rewind, the Th1/Th2 theory is one attempt at understanding immune regulation, and Th1 and Th2 cells are its key players.
This theory dates back to studies on mouse immune cells in the 80s. However, it is still considered controversial and it’s not without limitations and discrepancies [1].
According to the Th1/Th2 theory [1]:
- Th1 cells drive the so-called type-1 pathway (“cellular immunity”). They are thought to be involved in fighting viruses and other pathogens that enter cells, getting rid of cancerous cells, and triggering delayed-type hypersensitivity (DTH) skin reactions.
- Th2 cells drive the type-2 pathway (“humoral immunity”). They are hypothesized to increase antibody production and fight invaders that are outside cells. They may be involved in tolerance of organ transplants (xenografts) and of the fetus during pregnancy
But the human immune system is incredibly complex. We have many other types of immune cells that are orchestrated by various factors — from our encounter with microbes, to our health status, genetics, mood, and more.
That’s where Th17 cells come in. These cells were identified only recently and scientists think they can fill the missing gaps and explain some inconsistencies with the Th1/Th2 theory [2].
For example, Th17 cells are implicated in several human diseases and their cytokines are linked to inflammation and tissue damage [2].
In turned out that about a third of the progenitors — T helper cells — develop into Th17 cells, a third into Th1, and a third into Th2 cells [2].
However, Th17 science is new and the findings so far have been inconclusive. Let’s take a look at how much we know about this newly-discovered immune pattern.
Overview
T helper cells start off as “naive” T cells and can turn into Th1, Th2, or Th17 cells.
A naive T cell can either become an inflammatory Th17 cell or an anti-inflammatory Treg cell. According to some researchers, the goal in inflammation is to convert more Th17 cells to Treg cells [2].
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 we’ve spoken about [3].
Scientists claim that 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 may determine if these Th17 will cause disease, though more research is needed [3].
IL-1β can also increase the production of Th17 cells [4].Th17 cells produce the cytokine IL-17, as well as TNF and others [5].
Link to Kynurenine
Kynurenine is a metabolite of the amino acid tryptophan, used by the body while producing niacin. Recently, this pathway has been linked with everything from inflammation to immune imbalances and brain disorders [6].
Studies are still trying to decipher its impact on disease and whether it can be a therapeutic target [6].
Scientists think that IL-17 increases kynurenine (so does cortisol, IL-1, TNF, and IFNy/Th1 dominance) [7].
Limited data linked IL-17 to IBS [8]. However, the effects of increasing this pathway are mixed. Some animal studies suggest that it increases oxidative stress and may be associated with low mood [9].
Kynurenine can 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, some scientists hypothesize that kynurenic acid can reduce intelligence [10]. On the other hand, inhibiting Kynurenic acid seems to result in cognitive enhancement in mice [11]. Although intriguing, human data are needed.
Other Pathways
Interleukin 17 acts antagonistically with TNF and IL-1 [12] (antagonism is the opposite of synergy).
In some studies, IL-17 was associated with allergic responses. Researchers found that it induces the production of other inflammatory compounds (such as IL-6, IL-1β, TGF-β, TNF, IL-8, MCP-1, and PGE2) that is thought to lead to negative events like airway narrowing in people with asthma [12].
Th17 cells seem to have a circadian rhythm. The amount of Th17 cells changes during the day-night cycle. Animal studies suggest that the production of Th17 is higher at midnight than at noon [13].
Science reminds us that Th17 and IL-17 aren’t just “bad,” though.
Based mostly on animal findings, Th17 appears to have a protective role in combating fungi [14] and some bacterial infections (“extracellular”) [15], along with Tregs [15].
Researchers are investigating whether Th17 may have anticancer properties, but studies are still in the early phases. Other scientists speak of the “cancer and autoimmune trade-off,” but this theory is still filled with inconsistencies, leaving us with more questions than answers [16].
Additionally, Th17 cells appear to be resistant to the suppressive effects of Tregs [17, 18].
Studies in animal models of MS suggest that Th1 cells are important in initiating acute attacks, while Th17 cells are hypothesized to be more important in mediating the progression of this disease. This hasn’t been confirmed in humans, but one study found higher IL-17 expression in chronic versus acute MS lesions [19].
Limited data suggest 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. Large-scale studies are needed [20].
A normal range of IL-17A has yet to be defined. One study proposed levels of 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). More research is needed [21].
Gender Differences
Studies suggest that women are more susceptible than men to 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) [19].
The higher female prevalence of these diseases may be related to the fact that women might develop more robust immune responses than men [19].
Limited studies have suggested that men are more prone to Th17 and Th2 dominance, while women are thought to be more prone to Th1 dominance. However, there’s no hard evidence to back this up [22, 19].
For example, one study found that women have higher levels of Th1 cells, IgM, and CD4+ cell counts, and show stronger immune response responses to vaccinations. Other studies had mixed findings [19].
Additionally, studies indicate that pregnancy is a Th2 state. Scientists think that lower Th1 activity is part of the adaptive physiological response that women go through in pregnancy [1].
This is said to prevent the mother’s antibodies from mounting an attack against the fetus. It’s also thought to explain why women are more prone to infections during pregnancy. Many women with rheumatoid arthritis — typically seen as a Th1 disease — experience relapses after pregnancy [1].
On the other hand, male sex hormones or androgens may increase PPAR alpha, which causes inhibition of Th1 dominance in animals. At the same time, men tend to have lower PPAR gamma, which is hypothesized to lead to Th17 dominance [22].
To some extent, researchers believe that Th1 and Th17 “compete” with each other, but this is also uncertain. Some studies indicate that IL-2 produced by Th1 cells activates STAT5, which competes with STAT3 (thought to be produced in Th17 dominance) [22].
In line with this, the castration of male mice enhances Th1 autoimmunity and lowers Th2 cytokine production. We can’t extrapolate these findings to humans [19].
All in all, more human research on these gender-related mechanisms is needed.
Diseases Associated With Increased Th17
The majority of studies covered in this section deal with associations only, which means that a cause-and-effect relationship hasn’t been established.
For example, just because autoimmune diseases have been linked with increased Th17 activity doesn’t mean that and autoimmunity is caused by Th17 dominance. Data are lacking to make such claims.
Also, even if a study did find that Th17 activity contributes to autoimmune diseases, Th17 cells are highly unlikely to be the only causative factor. Complex autoimmune disorders always involve multiple possible factors – including biochemistry, environment, health status, and genetics – that may vary from one person to another.
Additionally, some of the studies listed below rely on animal experiments, which can’t be applied to humans. More research is needed before we understand how Th17 cells affect health in humans.
- Several Autoimmune diseases: Hashimoto’s [23], Grave’s [24], Multiple Sclerosis [25], Lupus/SLE [26], Uveitis [27], Type 1 diabetes [28], Systemic Sclerosis [29], Autoimmune myocarditis [29], Vitiligo [30]
- Heart disease [31, 32] (IL-17) – contradictory [26]
- IBS [33] – some cases
- Rheumatoid arthritis [34, 29]
- Hashimoto’s [35], Graves [35]
- Multiple Sclerosis [25]
- Asthma [36], Airway inflammation [37]
- IBD [29]: Crohn’s [38], Colitis [39]
- Sleep apnea [40, 21]
- Skin: Acne Lesions [41], Psoriasis [29], Eczema[42]
- Some cancers (extremely limited data) [43]
- Fibromyalgia [44] – increased IL-17A
- Osteoporosis in menopausal women [45, 46]
- Depression [47] (IL17 and TGFbeta1) [48]
- Periodontal Disease [29]
- Lyme arthritis. Lyme or B. burgdorferi seems to increase IL-6, IL-1b, IL-23, and TGFb, which increases Th17 immunity and may trigger Lyme arthritis [49].
- Stroke damage (IL-17) [50]
Th17 overactivity is hypothesized to lead to infertility in women because the Th17 response makes the immune system attack sperm [51].
On the other hand, Estradiol (E2) inhibits Th17 cell responses, so that sperm is not attacked during ovulation. Some scientists say this sheds light on the connection between fungal infections (which increase Th17) and female infertility, but proper data are lacking to back up this whole Th17-infertility theory [51].
Th17 is lower in chronic fatigue syndrome. A cause-and-effect relationship hasn’t been established [52].
Exceptions to the Rule
The Th1/Th2 theory states that overactivation of either the Th1 or the Th2 pattern can cause disease. Similarly, either pathway is thought to down-regulate the other [1].
Based on this, some studies claim that most substances that decrease Th1 will increase Th2 and vice versa (decreasing Th2 will increase Th1), but this isn’t always the case.
To expand this theory, substances that inhibit Th1 cells are usually thought to also inhibit Th17 cells. But as usual, there are some exceptions.
For example, Lithium only inhibits Th1 but not Th17 in cells and mice [53].
IL-17 is one of the main cytokines released by Th17 cells. Theoretically, inhibiting this cytokine blocks damage caused by these cells, but this still hasn’t been proven in humans.
There are two proteins that allow the cytokine IL-17 to be produced: STAT3 and Nf-kB [54]. We discuss factors that inhibit Nf-kB in this article. Below, we’ll dive into the research behind STAT3 inhibition.
Factors that May Balance Immunity (Inhibit Th17 and IL-17)
When to See a Doctor
If your goal is to lower your Th17 response because you have serious immune problems — including autoimmunity, and constant fatigue or pain — it’s important to talk to your doctor, especially your symptoms are significantly impacting your daily life.
Your doctor should diagnose and treat any underlying conditions causing your symptoms.
Research Limitations
Remember that the existing evidence does not suggest that Th17 dominance causes autoimmunity.
You may try the strategies listed below if you and your doctor determine that they could be appropriate. Read through the factors we bring up and discuss them with your doctor before trying them out. This is particularly important if you plan to take any dietary supplements.
Most of the lifestyle, dietary, and supplement factors listed below rely on animal and cellular data. These findings can’t be applied to humans. Clinical research is needed before the safety and effectiveness of any approach listed below is determined.
Thus, we’re providing a summary of the existing research, which should guide further investigational efforts. The studies listed below should not be interpreted as supportive of any health benefit.
Additional Precautions
Supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.
Additionally, supplement-drug interactions can be dangerous and, in rare cases, even life-threatening. That’s why it’s so important to consult your healthcare provider before supplementing and let them know about all drugs and supplements you are using or considering.
People who think they are Th17 and Th1 dominant may have an underlying, active infection. Inhibiting the Th1/Th17 system should be avoided as it may lower immunity and worsen the infection.
People with weakened immune systems, such as HIV patients, people on immune-suppressing medications, and the elderly should avoid approaches that lower Th1/Th17 activity.
Dosage may also matter and different doses will have different effects on immune balance. Safe supplement doses should not be exceeded.
Finally, have in mind that none of these strategies should ever be done in place of what your doctor recommends or prescribes.
Lifestyle
- Reduce stress [55]
- Sun/UV Exposure [56] and Nitric Oxide [57] – but not Th1
- Exercise [58]
- Keeping a Circadian Rhythm [59]
- Cold Acclimation [60]
Diet
- Avoid lectins [61]
- Fish oil [62] (reduced the surface expression of both IL-6R and IL-23R)
- Broccoli sprouts/Sulforaphane [63]
- One meal per day (in response to LPS) [64]
- Coffee [65]
- Kombucha/Lactic acid [66] (but they may increase IL-17A)
Nutrients
- Vitamin A/Retinol [67, 68] (RAR alpha)
- Zinc [69], (STAT3-)
- Vitamin D3 [70], (via increasing C/EBP homologous protein)
- Potassium [71]
- Folate [72] (deficiency caused Treg cells reduction in animals)
- Chromium [73]
Supplements
- Probiotics: L. salivarius [74], L. plantarum [74]
- Curcumin [75] – IL23, IL17 [76]
- Berberine [77]
- EGCG [78]
- Ursolic acid [79]
- Andrographolide [80]
- Black Cumin Seed Oil
- Olive leaf extract [81, 82]
- Fisetin [83] (inhibits IL-17)
- Chinese Skullcap/Baicalin [84, 85] (Number of Th17 and IL-17)
- NAG [86]
- Red Yeast Rice/statins [20] – synergizes with corticosteroids
- Grape Seed Extract [87, 88] (STAT3-)
- Boswellia [89]
- R-Lipoic Acid [90]
- Epimedium/Icariin [91]
- Apigenin [92]
- Honokiol [93]
- CBD [94]
- Galantamine [95, 96, 97]
- Huperzine A [95]
- Butyrate [98] – but increases it in response to an infection [99]
- Cinnamon/NaB [100] (increases IL-17)
- Artemisinin [101]
- Beta-Caryophyllene [102]
- Resveratrol* [103, 104] (conflicting)
- Probiotics: Enterococcus faecalis [105], (Mice)
- Parthenolide [106] – IL-17A [107]
- Ancient Wheat [82]
- Licorice/Lico A [108] (uncertain) [109]
- Ginger extract [110]
Experimental
The following factors are theoretical. They aren’t backed up by solid science. We bring them up for informational purposes.
Additionally, have the following limitations in mind:
- Metformin, methotrexate, hormones, and other medications should only be used with a doctor’s prescription.
- Nicotine is a harmful and addictive substance. It should only be used as part of cessation therapy in people who want to quit smoking.
- THC is illegal in many states and it has potential for harm and addiction.
- Brain chemistry is not something that people can change on their own with information from blog posts.
Hormones and Neurotransmitters
Drugs
Pathways
Scientists are investigating whether the following pathways reduce Th17 patterns in animals and cells:
- CB2 Receptor activation [120]
- PPAR delta [121]
- PPARgamma [122]
- Vitamin D receptor [68]
- RAR alpha [68]
- LXR [123]
- DRD5 (-) [124]
- STAT3 (-) [69]
- STAT1 (-) [91]
- HDAC (-) [125]
- IDO (+) [126]
- DPP4 (-) [127]
- mTORC1 [128]
- Acetylcholinesterase (-) [95]
- Cyp11a1 (-)
- RORyt (-)
- HIF1a (+) [129]
- AKT(-) [130]
- Dopamine d1R(-)… (inducible)… mTORC2(-) (natural)
- IL-1b (-) [89] – central role [131]
- IL-6 (-) [132] – central role [131]
- IL-23 (-) [132] – central role [131]
- TGF-b (-)
- H4R (-) [133]
- NF-kB (-) [67]
- GSK3 (-) [134]
- IL-17 (-) [135]
- IL-21 (-) [131]
- IL-10 (+)
- TNF (-) [131]
- IFN-b [136]
- IFNy [137]
- IL-12 [138]
- IL4 [138]
- PGE2 (-) [139]
- CD5 (-) [140]
Human data are lacking.
Factors that May Disrupt Immune Balance (Increase Th17)
Many unhealthy habits can disrupt immune balance.
It’s always a good idea to avoid unhealthy behaviors — such as smoking, fast food, overeating, being under a lot of stress, and drinking too much — that can bring your immune system out of balance.
Look to get regular exercise, enough nutrients, sleep, and follow a healthy circadian rhythm.
Below are some unhealthy lifestyle choices and foods that have been linked with Th17 overactivity in limited studies.
Additionally, have in mind that increasing Th17 is not always bad.
The body needs Th17 cells to fight off infections. Th17 activity also sometimes improves blood circulation (NO). That’s why it’s not so easy to target Th17 pathways — experts are still not sure about how beneficial it would be and in which cases [141, 142].
That’s why it’s important to discuss your overall symptoms and health goals with your healthcare provider. The goal is not necessarily to reduce Th1/Th17 but to balance the immune system as a whole.
Lifestyle
- Chronic psychological stress/anxiety. In a sentence, chronic stress is hypothesized to worsen Th17 overactivity and cause cortisol/glucocorticoid “resistance” [143].
- Cortisol resistance has been linked with autoimmune/inflammatory issues. Some scientists claim that these issues might, theoretically, worsen before they start to improve when people reduce stress. It’s thought that higher levels of cortisol may be needed to suppress the immune system in this case.
- Stress causes epinephrine to be released, which is hypothesized to lead to a dominant Th2/Th17 profile. Stress is claimed to affect inflammatory conditions by favoring Th17 immunity, but more data are needed [144].
- Scientists claim cells from anxious individuals show Th17 dominance (higher amounts of IL-17 and TNF), but clinical data are lacking. In healthy people, glucocorticoids/cortisol decreased excessive Th17 activation, but not in highly stressed people. Anxious people seemed to become insensitive to glucocorticoids [145].
- Adrenaline, which is a Beta2-AR agonist, may aggravate IL-17-type immune response [146]. Asthma drugs may worsen this response but offer temporary relief. This pathway needs to be studied further.
- Marathons/Excess exercise [147]
- Obesity [148]
- Circadian Rhythm disruption [13]
- EMFs [149]
Diet
- Gluten [150]
- Iodine excess [151] High levels may result in Th1 elevation [23].
- Arginine [141]
- Frying oils/Smoking (both produce oxysterols) [152]. Also, the enzyme CYP27A1 turns cholesterol into bile and this enzyme can increase oxysterols and therefore Th17 dominance [153].
- High salt diet [154]
- Long-chain fatty acids [155]
Toxins/Infections
- Free radicals [156]
- Fungal infections [61]
- Viruses
- Intracellular and extracellular bacteria [157]
- Parasites [158]
- Heavy Metals: Cadmium, Mercury and probably Lead and Arsenic[45]
- Flu Viruses [159]
- Klebsiella pneumoniae, Citrobacter rodentium, Candida albicans, Listeria monocytogenes, Salmonella enterica, Mycobacterium tuberculosis [157]
- Chlamydia [160]
- Certain gut microbes [161]
Hormones
- Leptin [162] – leptin is elevated in obesity.
- Adiponectin [163] Increases Th1 and Th17 cells; known for its insulin-sensitizing effects. Limited studies indicate that it is present in inflamed tissues of patients with rheumatoid arthritis and inflammatory bowel disease.
- Aldosterone [164]. Aldosterone increases blood pressure. Scientists think it might promote Th17 immunity.
- Insulin [113]
- IGF-1 [113]
- Desmosterol, an in-between step to cholesterol production in the body [123]
Supplements
- Forskolin [139]
- Uric acid (in combination with IL1b and IL18) [165]
- Resveratrol [166] – contradictory
- NAD+/Niagen NAD. (seems to increase Th1 and Th17 cells but may decreases their harmful activity; more research is needed) [3]
- L Casei [167], S Boulardii [168], Bacillus Subtilis [168] (may increase IL-17)
Pathways
Genes and Th17
STAT3 and mTOR
Limited studies have associated certain variations in these genes with Th17 immunity.
STAT3 is a protein that binds to DNA and increases gene expression.
Scientists believe that STAT3 is essential for the production of the TH17 cells. Theoretically, reducing this protein is supposed to lower Th17 cells [169].
STAT3 is thought to play an important role in autoimmune and inflammatory diseases. See more about STAT3 and a list of potential natural inhibitors.
Increased mTOR may increase Th1 and Th17, hypothetically leading to increased intestinal inflammation [128].
mTOR may increase another protein called hypoxia-induced factor (HIF)-1α, which increases Th17 cells [170].
Some researchers think that inhibiting mTOR may decrease Th1 Cells.
Technical: mTOR increases glycolysis, which allows Th17 cells to proliferate. This might work through HIF1α. Blocking glycolysis inhibited Th17 development while promoting Treg cell generation. Human data are lacking [129].
Read this post on factors that may inhibit mTOR.
This is a good picture that shows how these four T Cells might interact.
