In this post, we’ll be adding additional context to our previous atopic dermatitis post. To start this off right, let’s begin with a high level overview.
Atopic dermatitis, traditionally referred to as eczema, is an autoimmune disorder that impacts 20-30% of the US population . It affects your quality of life and may require expensive means to manage symptoms. Looking under the hood of eczema, a picture begins to form.
Your body uses a series of mechanisms that lead to inflammation. These processes are natural - but certainly not simple. They’re many actors in play, but what’s important is that each actor is connected to another in a long series of chains. And like all chains - it can be broken. You just have to find the right link.
We at SciZenna wish we had all the answers - and so do many others. Therapies to treat eczema come and go - but the scientific picture of this autoimmune disease is becoming more defined.
So let’s dive into this head first. We’ll start with an introduction of our first key player, the lymphocyte.
Lymphocytes are a type of white blood cell - otherwise referred to as a type of “leukocyte”. There are various forms of lymphocytes, but when it comes to atopic dermatitis, we’ll focus on Th1, Th2, and the more recently discovered Th17 lymphocytes .
Th1 lymphocytes are responsible for the body’s immune response to infections, while Th2 lymphocytes are responsible for the immune response against irritants. Th17 lymphocytes are slightly unique - which we’ll address further on .
What makes lymphocytes so important to the inflammation process is what they produce - small messenger proteins called cytokines.
Cytokines are small messenger proteins that, based on some stimuli, will “message” other cells to carry out a certain function. In the case of inflammation - these proteins are what sound the inflammatory alarm .
Some cytokines increase inflammation (pro-inflammatory) and others decrease inflammation (anti-inflammatory). Depending on which cytokine is produced - an inflammatory response may or may not occur. We're going to focus on cytokines IL-4, IL-5, IFN-gamma, and IL-17. For additional background information - the “IL” stands for “interleukin” and “IFN” stands for “interferon”.
IFN-gamma is a cytokine produced by the Th1 lymphocyte. It’s production is associated more with infections. IL-4 and IL-5 are type Th2 cytokines - meaning produced by Th2 lymphocytes . These cytokines are associated with irritation traditionally. And last but not least, IL-17 cytokine is produced by the Th17 lymphocyte.
What’s unique about this cytokine/lymphocyte pair is that IL-17 production can negatively regulate IL-4 and IFN-gamma production. Simply put, IL-17 can regulate the severity of the Th2 response. More importantly, IL-17 production has been shown to increase IL-4 production and Immunoglobin E production. And reduction of IL-17 has been shown to reduce dermatitis . This is extremely useful information that we’ll continue to explore
So we just introduced Immunoglobin E - let's dive deeper into that.
Immunoglobin E, also referred to as IgE, is an antibody that when produced, will lead to the classic symptoms of inflammation. Traditionally, the higher the IgE concentration present - the more severe the dermatitis . We’ve mentioned IgE in a previous post as well, and it occupies the spotlight when it comes to atopic dermatitis.
Although we can’t promise we won’t be introducing more actors - this is a great start. Let’s begin to focus on how these actors are connected, and where links between these actors can be broken.
As we described earlier - during times of infection or irritation, Th1 lymphocytes will produce cytokines including IFN-gamma and Th2 lymphocytes will produce cytokines IL-4 and IL-5. Atopic dermatitis has traditionally been recognized as a Th2-centered disease, meaning overproduction of Th2 associated cytokines . However, this picture is beginning to change.
Atopic dermatitis can be distinguished by the defects seen in the epidermal barrier. These defects can allow antigens to penetrate the skin barrier, which then induce an immune response.
This immune response will create a series of events including the activation of Th17 lymphocytes - which leads to the production of IL-17. As we alluded to earlier, IL-17 is unique in that it can upregulate Th2 lymphocytes, leading to an increase in IL-4, IL-5, and IgE production.
For individuals without atopic dermatitis, an immune response from an epidermal defect will primarily produce Th1 cytokines such as IFN-gamma (an immune response based on an infection) - however, individuals with a history of atopic dermatitis will produce Th2 lymphocytes and its associated cytokines. This is where atopic dermatitis becomes a chronic disease .
When IL-4 and IL-5 cytokines are produced, they alert neighboring leukocytes (white blood cells) to produce IgE (Immunoglobin E) antibody.
IgE production starts another series of chains involving leukotrienes (specifically LTB4, also a cytokine) and mast cells (cells that are rich in various other immune response inducing proteins) - which then leads to the production of inflammatory free radicals that sustain skin inflammation . This skin inflammation can be quite itchy - and with another scratch, the cycle starts again.
In a simplistic overview, IL-17 is produced based on disruption of the epidermal barrier. This leads to Th1 and primarily Th2 cytokine production. These cytokines then trigger white blood cells to produce IgE, which leads to production of LTB4, which leads to a sustained inflammation response due to overproduction of free radicals, and ultimately ends with itchy skin . When the skin is scratched, disrupting the epidermal barrier again, the cycle starts over.
As this cycle goes on, it’s postulated that the relationship between Th1 and Th2 cytokine production begins to favor Th2 - leading to more and more severe symptoms. So how can the chain be broken?
Well, although there are quite a few actors involved - they traditionally rely on a few common characteristics. Specially, free radical generation and reactive oxygen species (ROS) .
Inflammation requires unstable molecules to be produced, almost like gasoline or electricity for your car. Without these unstable compounds - the inflammation car doesn’t drive, and the chain is broken.
Reactive oxygen species are also common in the inflammation chain - this is based on the molecular structures of interleukins and leukotrienes. Oxygen is a primary fuel to progressing these reactions .
What researchers are now investigating are the roles of antioxidants and free radical scavengers in reducing atopic dermatitis. And one of the candidates emerging is Black Seed Oil, and its active compound - Thymoquinone (TQ).
Discovered in the 1960s, Thymoquinone was quickly identified as a free radical scavenger and super antioxidant . Basically, the antithesis of inflammation. We’ve pulled together quite a bit of background information on Black Seed Oil and Thymoquinone - as far back as ancient Egypt.
Qualitatively, topical application of Black Seed Oil has been shown to reduce the severity of hand eczema and improve the quality of life of patients . We have dived into the research previously - so it's time to dive into new research to see what else may be occurring.
The first actor of focus is IL-17. This cytokine is unique because it can affect the amount of other inflammation producing cytokines - leading to greater levels of inflamed skin. More IL-17 present ultimately leads to greater IgE production and more severe skin inflammation .
In a study published by Florida A&M University in the Journal of Neuroimmunology, researchers examined the effects of Thymoquinone on various inflammatory markers, including IL-17 and IL-4. In this study, the focus was on neuroinflammation and the production of cytokines by microglia. Microglia are the brain’s and central nervous system’s cells first line in defense when an immune response is required .
The researchers activated the immune response for these microglia cells, and treated half of the activated cells with Thymoquinone and half without Thymoquinone. The researchers also had a group of control cells that were not activated.
In summary, the untreated, activated microglia cells had a 127% increase in IL-17 production and 151% increase in IL-4 cytokines compared to the control, inactivated cells. Clearly indicating a strong inflammatory response was underway .
However, with Thymoquinone - things changed. The activated, inflamed cells’ IL-4 cytokines were reduced by 19% compared to the untreated inflamed cells. Great news! But it gets better...
Thymoquinone took things a step further. By treating the inflamed microgila cells with Thymoquinone, Thymoquinone reduced IL-17 cytokines for the inflamed microglia cells to 2% LOWER than the control, uninflamed cells .
Meaning, not only did Thymoquinone reduce inflammatory cytokines for the untreated, inflamed cells - it reduced IL-17 to that below the control, non-inflamed cells. This is very exciting news because as we mentioned earlier - IL-17 is becoming a more prominent figure when it comes to atopic dermatitis. Greater production of IL-17 leads to increased production of other inflammatory cytokines, resulting in a compounding effect. This research study highlights that by reducing IL-17, Thymoquinone is capable of reducing inflammation further upstream, resulting in greater impact .
So Thymoquinone reduces IL-17 cytokine expression - but how does Thymoquinone stack up against IL-4, and IL-5? Remember, greater expression of inflammatory cytokines leads to greater levels of itchy, uncomfortable skin.
Research published in the Journal of Molecular Immunology examined the effects of topical Thymoquinone on the ears of mice with eczema. The researchers specifically looked at the change in concentration of IL-4, IL-5, IFN-gamma, and IgE antibody of mice with and without topical TQ treatment .
As expected - inflammatory mediators were greatly reduced following TQ treatment. Specifically, the untreated eczema group had 189% higher expression of IL-4 and 198% higher expression of IL-5 cytokines compared to the control, non-eczema mice.
Now for the kicker - Topical TQ was able to reduce IL-4 cytokine expression of mice with eczema to 13.9% less than the control, non-eczema mice . That’s dramatic - no longer did the eczema mice have almost twice the expression of IL-4 compared to the control mice - they actually expressed less cytokines than the control mice!
IL-5 and IFN-gamma levels were also reduced. IL-5 was reduced to 139% (originally 198% higher than the control) and IFN-gamma was reduced to 158% (originally a massive 602% higher than the control group).
Last but certainly not least, topical TQ reduced IgE concentration from 2177 ng/mL (untreated eczema affected mice) to 693.6 ng/mL. The control group that did not have eczema had an IgE concentration of 591.4 ng/mL - only slightly higher than the TQ treated eczema mice .
Thus far, we’ve highlighted research suggesting that topical TQ (Thymoquinone found within black seed oil) was able to reduce IL-4, IL-5, IFN-gamma, and IgE for mice with eczema as well as reduce IL-17 cytokines in inflamed cells.
We’ll look at the final actor LTB4 and the effect Thymoquinone has on its activity.
As a refresher, LTB4 is a leukotriene produced by leukocytes and plays a significant role in the inflammatory process. Similar to interleukins, leukotrienes also convey messages between cells, and can initiate the production of inflammatory cytokines.
LTB4 is unique in the sense that its purpose is to promote free radical generation and extend tissue inflammation . More or less the worst role to play when it comes to atopic dermatitis. Theoretically, by reducing LTB4 production, tissue inflammation can relax more quickly.
Now for the logistics. Production of LTB4 is carried out by an enzyme called 5-lipoxygenase. 5-lipoxygenase relies on free radicals and oxygen rich fatty acids to produce LTB4. Keep this in mind as we’ve already described that Thymoquinone is an active free radical scavenger and super antioxidant.
Researchers from the Karolinska Institutet in Sweden as well as Al-Azhar University in Egypt tested Thymoquinone at various concentrations against cultured human white blood cells and monitored the leukotriene activity for these cells.
What the researchers found was surprising, yet simple. As the concentration of Thymoquinone was increased (from 1 micromolar to 100 micromolar), LTB4 concentration decreased with it. Compared to the control, untreated white blood cells - leukotriene concentration was reduced by 50% even at the lowest concentrations of 1.3 - 2.8 micromolar.
In short, Thymoquinone was reducing the available free radicals and oxygen rich species required to produce LTB4 - starving 5-lipoxygenase of its raw ingredients. As more Thymoquinone was used, more free radicals were scavenged, and less LTB4 was ultimately produced.
Although far from a simple process - there is a greater understanding of atopic dermatitis forming in the scientific literature. What’s important to understand is that there is a common mechanism that allows inflammatory processes to occur - this mechanism relies on various actors to communicate with each other, and the production of these actors relies on free radical generation and reactive oxygen species.
By quenching free radicals and reducing reactive oxygen species - the scientific literature agrees that atopic dermatitis can be reduced. The only question is - what is the most effective way to do this?
The key word is effective - not expensive. Expensive treatments are traditionally expensive because of complicated business principles and intellectual property. Competition is snuffed out by legal barriers and therefore prices skyrocket.
We at SciZenna believe there are alternatives to expensive treatments. And we believe that Black Seed Oil may be just the start to understanding the inflammatory process and it’s break points.Citations:
- Eczema (Atopic Dermatitis). (2017, April 17). Retrieved April 27, 2020, from https://www.niaid.nih.gov/diseases-conditions/eczema-atopic-dermatitis.
- Klonowska, J., Gleń, J., Nowicki, R. J., & Trzeciak, M. (2018). New Cytokines in the Pathogenesis of Atopic Dermatitis-New Therapeutic Targets. International journal of molecular sciences, 19(10), 3086.https://doi.org/10.3390/ijms1910308
- Aslam H, Shahzad M, Shabbir A, Irshad S. Immunomodulatory effect of thymoquinone on atopic dermatitis. Mol Immunol. 2018;101:276–283. doi:10.1016/j.molimm.2018.07.013
- Mahmoud Mansour & Susanne Tornhamre (2004) Inhibition of 5-lipoxygenase and Leukotriene C4 Synthase in Human Blood Cells by Thymoquinone, Journal of Enzyme Inhibition and Medicinal Chemistry, 19:5, 431-436, DOI:10.1080/14756360400002072
- Cobourne-Duval, M. K., Taka, E., Mendonca, P., & Soliman, K. (2018). Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFκB pathway signaling targets in LPS/IFNγ -activated BV-2 microglia cells. Journal of neuroimmunology, 320, 87–97.https://doi.org/10.1016/j.jneuroim.2018.04.018
- El–Dakhakhny, M. (1963). Studies on the Chemical Constitution of Egyptian Nigella SativaL. Seeds. The Essential Oil. Planta Med 1963; 11(4): 465-470.DOI: 10.1055/s-0028-1100266
- Yousefi M, Barikbin B, Kamalinejad M, et al. Comparison of therapeutic effect of topical Nigella with Betamethasone and Eucerin in hand eczema. J Eur Acad Dermatol Venereol. 2013;27(12):1498–1504. doi:10.1111/jdv.12033