A Simplified Look At Messenger Molecules

(or… Don’t Shoot the Messenger!)

Let’s get something straight right up front: cytokynes are not a toxin or a disease or something bad to be stamped out. They are just messengers.

Cytokines are not the disease or infection or insult, they are the message that is created by white blood cells (lymphocytes and macrophages), epithelial cells (cells that line internal tissues) and by other cells in lesser degrees, in response to some insult like a bacteria, virus or other infection. They can cause inflammation and are also created in response to inflammation.

Cytokines are the way that cells in distress call other cells for help — like an S.O.S.

When our immune system is fighting pathogens, cytokines call immune cells such as T-cells and macrophages to travel to the site of the infection.

Measuring cytokines gives us an indication of what is going on that would cause our cells to be calling for help.

When we talk about lowering inflammatory cytokines what we really should be talking about is addressing the cause of the inflammation so that cytokine-producing cells no longer feel the need to send out “help me!” messages.

Cytokines work on a “negative feedback” system. When there is a stimulus (a reason for cells to need help), cytokines are produced. The greater the stimulus, the more cytokines are produced. If the stimulus becomes less (when the infection heals or the inflammation subsides), cytokine production decreases because less are needed. Like the gas pedal on your car, to go faster you press harder – if you remove your foot (removing the stimulus) the engine slows down and the car stops.

Occasionally the cytokine response can become unbalanced, entering a sort of positive feedback loop which can easily get out of control – imagine if your car’s gas pedal worked the other way, where you had to keep it pressed down to stop! This has been termed a “cytokine storm” and is a serious medical emergency that can result in organ damage and even death. It is one reason for the deaths of people with otherwise healthy immune systems in pandemics such as the Spanish Flu of 1918 or the more recent Bird Flu and Swine Flu outbreaks.

There are three broad categories of cytokines – they can be grouped according to what they do, though there is also a lot of redundancy and “cross training” going on with cytokines.

First, there are Cytokines involved in innate (as in “born with it”) immunity and inflammation. Most of these cytokines are made by macrophages (important for removing pathogens), mast cells (important to inflammation) and endothelial cells (the cells that line our blood vessels and lymphatic system).

Major players here include:

  • TNF (tumor necrosis factor) and interleukin-1 (IL-1) help to activate endothelial cells.
  • Chemokines serve to attract different kinds of leukocytes (infection-fighting white blood cells)
  • IL-12 and interferon-gamma (IFN-y) are more involved in chronic inflammation.

Then there are cytokines involved in adaptive (as in “acquired in response to an infection or vaccination”) immunity. Most of these cytokines are made by our T helper cells (T cells are a kind of lymphocyte that matures in our thymus gland – hence the ‘T‘).

There are 2 main kinds of T Helper cells:

  • Th1 cells: Type 1 helper T cells make pro-inflammatory cytokines like IFN-y, IL-2, and TNF. These cells are involved in cell-mediated immunity and the cytokines produced by them stimulate the breakdown of microbial pathogens. Several chronic inflammatory diseases like multiple sclerosis, diabetes, and rheumatoid arthritis are considered Th1 dominant diseases.
  • Th2 cells: Type 2 helper T cells produce the cytokines IL-4, IL-5, IL-9, IL-10, and IL-13. Th2 cells are involved in allergy responses. Cytokines like IL-4 stimulate antibodies directed at extracellular parasites and at viruses. IL-5 stimulates eosinophil (a kind of white blood cell) responses, also part of the immune response toward large extracellular parasites. Allergy is considered to be Th2 dominant condition.

While Th1 cells are generally thought to produce inflammatory cytokines and Th2 cells are thought to produce inflammation-mediating cytokines, as you can see here there is “crossover.”

  • IL-2 and IL-4 cytokines tell lymphocytes to proliferate and differentiate (that means to grow, mature, and take on a specialized function).
  • IFN-gamma and IL-5 cytokines send messages that activate other cells.

Then there are cytokines involved in hematopoiesis – a fancy word that means “building new blood cells” – either oxygen-carrying red blood cells or infection-fighting white blood cells. Cells that make these cytokines include endothelial cells, macrophages, and other cells in our immune system. An example of this are colony-stimulating factors like G-CSF (granulocyte-colony stimulating factor) which causes hematopoietic cells to grow.

These are just a few of the more broad classes of cytokines – there are hundreds of these chemical messengers, each with a unique purpose and job to do.

Some of the ones we hear about most often are:

  • TNFa or Tumor Necrosis Factor alpha. While the name sounds ominous, TNF is a vital player in our response to infection. Its primary role is the regulation of immune system cells. TNF is able to induce fever, cause cell death, cause cachexia, initiate inflammation and to inhibit tumor growth and viral replication in response to sepsis or infection.
  • Interleukin 6 (IL-6) is an cytokine that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine (produced from muscle cells). [could this get any more confusing?] While IL-6 serves to stimulate the inflammatory and auto-immune processes in many diseases it also is anti-inflammatory in that it moderates or mediates inflammation by inhibiting TNF-alpha and IL-1, and by activating other interleukins such as IL-10.
  • Interferon gamma (IFNγ or type II interferon) is a cytokine that is critical for both innate and adaptive immunity against viral and some bacterial and protozoal infections. IFNγ activates macrophages. If IFNγ becomes uncontrolled it can be associated with a number of auto-inflammatory and autoimmune diseases. Its importance in the immune system comes from its ability to inhibit viruses directly, and most importantly from its stimulating and modulating effects on immunity. IFNγ is produced mainly by natural killer (NK) and natural killer T (NKT) cells.
  • Interleukin 10 (IL-10) is an anti-inflammatory cytokine. IL-10 inhibits production of pro-inflammatory cytokines like as IFN-γ, IL-2, IL-3, TNFa and GM-CSF made by cells such as macrophages and T-cells. IL-10 is important for counteracting hyperactive immune responses that can occur with over-stimulation of pro-inflammatory cytokines.

Importantly, we need to remember that many of the inflammatory cytokines are induced by oxidative stress – meaning that antioxidants play an important role in reducing the production of inflammatory cytokines.

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen that form when cells metabolize oxygen. In normal amounts ROS have important roles in cellular health. In times of stress (exposure to pathogens, toxins, UV or heat, ionizing radiation, etc.), ROS levels may greatly increase which can damage cells. This is known as oxidative stress and ROS are sometimes called “free radicals.”

Also remember that cytokines themselves trigger the release of other cytokines leading to increased oxidative stress. This makes them important in chronic inflammation, as well as other immune responses such as fever.

So, when your doctor presents you with your lab results and says “you have some high cytokines – we need to get those down,” he really means that there are some stresses going on – infection, chronic inflammation, allergy, oxidative stress, toxicity – that are being shown to him by the cytokines that can be measured. These stresses — the cause of elevated cytokines — are what must be dealt with in order to “bring down” the high cytokines, not the other way around. “Bringing down” high cytokines will not correct the insult (infection, toxicity, inflammation, etc.) that is causing the problem in the first place.

Maxi Flavone is formulated to “bring down” high cytokines – but not in a way that a drug might – by simply shutting down important cytokine production. Cytokines are very much a balance, and they are all important – even the inflammatory ones – so shutting down one or several could lead to some serious problems as a delicate balance is upset. Instead, Maxi Flavone, with its flavonoids and antioxidants, addresses the ROS and inflammation that is causing the release of inflammatory cytokines such as TNF-a.

Finding and correcting the reasons for inflammation such as environmental stresses (air pollution, mold, toxic exposure), subtle or sub-clinical infections (candida, chlamydia, amebiasis), personal stresses (job, sleep, relationships), physical stresses (allergies, food intolerances, hormone imbalances) and nutritional deficiencies or excesses is vital to correcting cytokine imbalances.

The truth is, though we talk a lot about cytokines, there are so many of them and their interactions are so complex that we really don’t have a good understanding of the many interactions and ways that they function. Trying to micro-manage cytokines with individual interventions is probably like throwing cups of water into the ocean to make the level rise.

What we DO know is that cytokines become imbalanced in response to identifiable “macro” insults or imbalances in the body: infections (subtle or obvious), stress (external and internal), toxins — anything that creates an alarm reaction in the body.

Instead of pretending that we understand cytokines and their myriad functions and interactions, a more productive path to health and fertility is to balance the body at the higher levels. The cytokines know how to balance themselves when everything “upstream” in the body is in balance and threats to physical health have been removed.


Th1 Stimulating Supplements:
Immune-boosting herbs such as echinacea, astragulus, licorice root, ashwaganda, panax ginseng, chlorella, grape seed extract, and common immune-boosting medicinal mushroom extracts, like maitake, reishi, and shitake, will stimulate Th1.

Th2 Stimulating Supplements:

Antioxidants like resveratrol, pycnogenol, curcumin from turmeric, genistein, quercetin, and green tea will stimulate Th2.

Vitamin D is increasingly being recognized for it’s importance in managing healthyTh1/Th2 balance and low vitamin D status is associated with an increased risk of Th1 mediated autoimmune diseases. It has been seen that Vitamin D deficient persons have elevated Th1 cell-associated responses and decreased Th2 cell-associated responses. The antiinflammatory effects of vitamin D are very similar to IL-10 – one o fthe most important antiinflammatory cytokines.

Fish Oil – (EPA / DHA) is highly antiinflammatory. EPA (eicosapentaenoic acid) decreases TNF-a.
EPA and DHA (docosahexaenoic acid) each decrease NK cell activity and this effect is synergistic when both EPA and DHA are used together.


Seydel KB1, Li E, Swanson PE, Stanley SL Jr. Human intestinal epithelial cells produce proinflammatory cytokines in response to infection in a SCID mouse-human intestinal xenograft model of amebiasis. Infect Immun. 1997 May;65(5):1631-9

Mullins BJ1, Kicic A, Ling KM, Mead-Hunter R, Larcombe AN.
Biodiesel exhaust-induced cytotoxicity and proinflammatory mediator production in human airway epithelial cells.Environ Toxicol. 2014 Jul 5

Xiong H1, Wei L, Peng B. IL-17 stimulates the production of the inflammatory chemokines IL-6 and IL-8 in human dental pulp fibroblasts.
Int Endod J. 2014 Jul 5

Sundman E, Olofsson PS. Neural control of the immune system. Adv Physiol Educ. 2014 Jun;38(2):135-9

de Vries MA1, Klop B, Janssen HW, Njo TL, Westerman EM, Castro Cabezas M. Postprandial inflammation: targeting glucose and lipids.
Adv Exp Med Biol. 2014;824:161-70

Ciortea R1, Mihu D, Mihu CM. Association between visceral fat, IL-8 and endometrial cancer. Anticancer Res. 2014 Jan;34(1):379-83

Ali Akoum, Christine Jolicoeur, Abdelaziz Kharfi, and Marie Aubé. Decreased Expression of the Decoy Interleukin-1 Receptor Type II in Human Endometriosis. Am J Pathol. Feb 2001; 158(2): 481–489

Margherita T. Cantorna, Sanhong Yu, and Danny Bruce. The paradoxical effects of vitamin D on Type 1 mediated immunity. Mol Aspects Med. Dec 2008; 29(6): 369–375.Published online May 4, 2008. doi: 10.1016/j.mam.2008.04.004 PMCID: PMC2633636 NIHMSID: NIHMS82537

Matheu V1, Bäck O, Mondoc E, Issazadeh-Navikas S. Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease.J Allergy Clin Immunol. 2003 Sep;112(3):585-92.

Margherita T Cantorna, Yan Zhu, Monica Froicu, and Anja Wittke. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system1,2,3,4. 2004 American Society for Clinical Nutrition

Mukaro VR, Costabile M, Murphy KJ, Hii CS, Howe PR, Ferrante A. Leukocyte numbers and function in subjects eating n-3 enriched foods: selective depression of natural killer cell levels. Arthritis Res Ther. 2008;10(3):R57. Epub 2008 May 14.

Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, Martin A, Andres-Lacueva C, Senin U, Guralnik JM. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab. 2006 Feb;91(2):439-46. Epub 2005 Oct 18.

Sundrarjun T, Komindr S, Archararit N, Dahlan W, Puchaiwatananon O, Angthararak S, Udomsuppayakul U, Chuncharunee S. Effects of n-3 fatty acids on serum interleukin-6, tumour necrosis factor-alpha and soluble tumour necrosis factor receptor p55 in active rheumatoid
arthritis. J Int Med Res. 2004 Sep-Oct;32(5):443-54.

Yamashita N, Sugiyama E, Hamazaki T, Yano S.Inhibition of natural killer cell activity by eicosapentaenoic acid in vivo and in vitro.Biochem Biophys Res Commun. 1988 Jan 15;150(1):497-505.

Yamashita N, Yokoyama A, Hamazaki T, Yano S. Inhibition of natural killer cell activity of human lymphocytes by eicosapentaenoic acid. Biochem Biophys Res Commun. 1986 Aug 14;138(3):1058-67.

Yamashita N, Maruyama M, Yamazaki K, Hamazaki T, Yano S. Effect of eicosapentaenoic and docosahexaenoic acid on natural killer cell activity in human peripheral blood lymphocytes. Clin Immunol Immunopathol. 1991 Jun;59(3):335-45.

Thies F, Nebe-von-Caron G, Powell JR, Yaqoob P, Newsholme EA, Calder PC. Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y. Am J Clin Nutr. 2001 Mar;73(3):539-48.