INL Article - Cytokine regulation with basic nutritional interventions
This edition is to introduce the cytokines, which are the communication system of the immune cells. The aim is to understand some ways to modify these when needed in illness.
What is the Cytokine?
The term “cytokine” (Greek –cyto, cell, and –kinos, movement) is a general term for a group of proteins that can have a specific effect on movements and interactive communications between immune related cells. (1)
Apart from dendritic cells and T-helper cells, cytokines are also produced by macrophages, particularly TNF-a and NF-kB. These two are the most proinflammatory cytokines, inducing fever (with IL-6), causing leukocytosis (NF-kB), endothelial leucocyte adhesion molecule expression (IL-8), increasing vascular permeability, and activating local leucocyte and acute phase proteins.
Other macrophage cytokines include IL-1, IL-6, IL-12, all potent immune cell upregulating cytokines.
IL-1B plays an important role in stimulating macrphages, neutrophils, basophils, B and T cells. In IL-1B and IL-6 stimulating T cells activates Th17 T cells that in an acute infection can produce the antiviral IFN-g, as visualised below:
So we see that cytokines allow the different cells of the immune response work with each other as shown in the diagram below.
Modulation of immune function can be performed by up or downregulating these cytokines with nutraceuticals or pharmaceuticals. For example, numerous in vivo and in vitro studies have been shown that curcumin and its analogs markedly inhibit the production and release of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, TNF-α as well as NF-kB, and additionally upregulating IL-10, the immune modulator. (2)
How does the T-helper cell development system interact with cytokines?
T-helper cells from the thymus gland are important in the adaptive immune response. The mature helper CD4+ MHC II class cells help with B cell activation leading to secretion of most antibodies. Activation of the cytotoxic T cells (CD8+) MHC1, generally by dendritic cells, can initiate the CD8+ to kill virus-infected cells, cancer cells as well as other damaged cells. For infections the CD4+ are the more critical, so that the CD4+:CD8+ ratio should be over 1. (3)
CD4+ T-helper (Th) cells are activated by varied cytokines from antigen presenting cells (APC’s) that dictate whether it is Th1, Th2, Th17 or Treg cells that emerge from the thymus to act on other cells. (4) The diagram below represents the interaction between the cytokines and the main thymic cell types.
For instance bacterial or viral antigens may initiate a IL-12/IFN-g release from dendritic cells upon the Th0 naïve cells to cause a Th1 immune response, whereas some other irritants such as parasites or allergenic substances via the APC’s may initiate IL-4 and the Th2 system. Chronic extracellular bacterial overgrowth, commonly in the gut, can initiate the Th17 cell type. Since most active leucocytes secrete TGF-b, its presence should activate the Treg immune balancing process where IL-10 suppresses leucocyte activities, quenching inflammation.
The ratio of TNF-a : IL-10, if > 30 gives a good indication of Th1:Th2 dominance since TNF-a is a Th1 cytokine. (It is available in blood testing at Pathlabs).
Th1 & Th2 cells play a varied role in the immune system
People with autoimmune conditions such as multiple sclerosis (MS), diabetes and rheumatoid arthritis (RA) have been described as Th1 dominant, with excessive macrophage related TNF-a and IL-6, while in contrast, atopy and allergy are considered as Th2 dominant diseases. (5) Targeted Th1 drug treatments for suppressing TNF-a and IL-6 have been developed with some success. As mentioned nutraceuticals, such as curcumin, can also be employed which, although less potent than drugs, cause less side effects as they work more broadly in the regulatory systems.
It is IL-4 and IL-13 that are elevated in Th2 dominant cases, activating eosinophils, basophils and mast cells. Gamma Tocotrienols, Quercetin and Nigella sativa are therapeutic options to consider for downregulating the Th2 interleukins, with good results in allergic rhinitis and asthma, for instance. (6), (7), (8).
Interestingly this Th1:Th2 model starts to break down when looking for consistencies in immune response in Th1 or Th2 dominant patients. The discovery of the Th17 subset helped to further unravel our understanding.
Where does Th17 cells fit into the mosaic?
Th17 cells, discovered in 2003, are characterised by production of the IL-17, known to have multiple inflammatory effects on epithelial, endothelial and fibroblastic cells. (9) While Th17 T cells can play an important antiviral role in acute infection, recent studies have placed Th17 within the pathogenesis of a diverse group of chronic inflammatory conditions ranging from asthma, to inflammatory bowel disease or psoriasis.
It is believed that Th17 cells, which share half the receptor of Th1, may protect us from microbes that Th1 cells are not effective against, notably the extracellular bacteria (such as in the sinus, gut or bladder), as well as some fungi, such as Candida albicans. (10)
T-regulatory cells are the shepherds of Th1, Th2 and most importantly, Th17
It has been said that: “where Th17 cells cause, T-regulatory cells inhibit”. (11) T-reg cells are immune suppressive, opposing Th1, Th2 and Th17 activity, mostly via IL-10. Their main role is to establish and maintain immune tolerance. Hence in allergy, asthma, and autoimmunity, that - if immunological tolerance can be induced via the induction of T-reg cells - then chronic symptoms are abated. (12)
One interesting arena where Tregs can be activated is in the treatment of food allergy, with probiotics playing a large part in both IL-10 and T-regulatory production. In fact, we have already seen probiotic strains such as Bifidobacterium longum, probiotic Clostridia species and Bacteroides fragilis inducing intestinal T-reg cells that are capable of suppressing food allergy and colitis. (13), (14)
The anti-inflammatory and immune regulating IL-10 is also beneficially upregulated simply by regular exercise, sunlight and calorie restriction, as well as vitamin D3, curcumin, zinc and fish oils. Let’s now explore zinc and vitamin D further.
Vitamin D and Zinc can suppress Th-17 activity
Vitamin D3, via the vitamin-D receptor, has a novel role in the suppression of Th-17 cells. (15) This discovery has since been expanded in research in asthmatic children where Vitamin D was shown to reduce the differentiation and expansion of Th17 cells, via modulation of both T cells and dendritic cells. (16) Clinically asthma sufferers have less serious exacerbations of asthma when they have adequate Vitamin D3. (17)
Interestingly, another micronutrient that is often found in deficiency states in the chronically inflamed patients is Zinc and just like Vitamin D, plays an important role in Th-17 regulation. A study released in 2019 investigated the role that zinc deficiency played in driving Th-17 activity along with loss of T-reg cell function. The conclusion suggesting that balancing zinc levels was a fundamental component in halting the progression of autoimmune illnesses connected to Th17. (18) Zinc also opposes excessive NF-kB and TNF-a production so that its immune regulation benefits are widespread. (19)
High Sodium intake increases Th17 and makes T-reg cells less effective
Sodium has been found to have a stimulating effect on Th17. Excessive sodium consumption not only elevates pro-inflammation Th17 cells, augmenting autoimmune diseases and asthmatic reactions, but excessive sodium simultaneously inhibits the suppressive function of T-reg cells. (20) This has since been found to be compounded by zinc deficiency status.
This mechanism of action has now seen numerous studies outline the aetiology of autoimmunity back to a high salt diet. (21) Interestingly when studying this, researchers have found that people who ate out a fast food establishment more than once a week had higher levels of Th17 cells. (22) The high salt, low zinc problem is worthwhile to consider in the diets of the elderly, owing to their low protein-zinc intake, with a high salt and monosodium glutamate used for flavouring.
These findings driven by Professor Yehuda Schoenfeld have made the correction of dietary deficiencies and other dietary changes a major pillar in the “mosaic of autoimmunity.” (23)
Building our knowledge of the nutritional biochemical relationships inherit within the immune system holds the potential to unlock some of the most complex conditions our patients face today.
With multiple other environmental factors at play it seems that nutrition, the correction of dietary deficiencies in some cases and correction of over-consumption in others is well within the control of the health professional’s ability to assist their patient’s immune systems in varying ways.
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