Could This Gene Play A Role In Psoriasis? (STAT3)

The STAT3 gene codes for one member of a family of proteins called signal transducer and activator of transcription, or just “STAT” for short. STAT proteins are activated by other proteins (such as JAK), which causes them to bind to DNA to turn certain genes “on” or “off” [R].

When it comes to the STAT3 protein specifically, its main role is to control the expression of genes involved in the growth, development, and activation of immune system cells. This process is triggered by “messenger molecules” called cytokines. While STAT3 responds to many different cytokines, the main ones involved in psoriasis include IL-6, IL-17, IL-21, IL-22, and IL-23 [R, R, R].

The STAT3 gene encodes a protein that either activates or blocks the expression of genes required for the function of immune cells, depending on how the protein is activated.

STAT3 and Immunity Regulation

The immune system protects the body from infections and cancer under normal circumstances, but can also cause allergies and inflammatory/autoimmune disorders when imbalanced! STAT3 responds to cytokines that either activate or block the immune response — in other words, it is one of the mechanisms the body uses to fine-tune the immune system.

On the one hand, STAT3 contributes to the development and function of the cells that:

• Promote inflammation and kill microbes (neutrophils) [R, R]
• Present infectious particles to T-cells (dendritic cells) [R]
• Produce antibodies (B-cells) [R, R, R]
• Fight off infections, but which may cause autoimmune and inflammatory disorders if overactivated (Th17) [R, R, R]
• Quickly respond to repeated infections that the body has already developed immunity against (memory T-cells) [R, R]

STAT3 also activates the immune response by reducing the production of immunosuppressive T-cells (also known as “Tregs”) [R].

On the other hand, STAT3 can also act as an immunosuppressant by:

• Increasing the expression of its own blocker (SOC3) [R, R, R]
• Preventing the development of dendritic cells [R]
• Blocking the production of pro-inflammatory cytokines by white blood cells (neutrophils, macrophages, and dendritic cells) [R, R, R]
• Producing the B-cells that suppress defense and autoimmunity (commonly known as “Bregs”) [R]
• Helping Tregs block Th17 development [R, R]

The STAT3 protein plays a fine-tuning role in the immune system, as it can both stimulate or suppress the immune response under different circumstances.

STAT3’s Role in Psoriasis

Psoriasis is a chronic inflammatory condition of the skin presenting with red patches that are typically covered with silvery scales and may be itchy or painful. Psoriasis can be accompanied by many other conditions, the most common one being arthritis (developed by approximately one-third of patients). Others include heart disease, metabolic syndrome, kidney disease, mood disorders, and lymph system cancer [R, R].

Scientists think that psoriasis is an autoimmune condition in which skin components released by injuries or infections activate the cells that present infectious particles to T-cells (dendritic cells) to produce cytokines such as IFN-alpha, IFN-beta, TNF-alpha, IL-6, and IL-23, which in turn triggers skin inflammation and thickening [R, R, R].

Of these, IL-6 and IL-23 play a key role in STAT3-associated psoriasis. Upon activation by these cytokines, STAT3 promotes the development of immature T cells into Th17 and their ability to produce the pro-inflammatory cytokine IL-17 [R, R, R, R].

In addition, the activation of STAT3 by IL-6 inactivates immunosuppressive Tregs, further worsening inflammation in people with psoriasis [R, R]. IL-6 also promotes the production of the cytokine IL-21, which not only activates STAT3 but also stimulates its own production and amplifies IL-23 activity (by increasing the production of its receptor IL-23R) [R]. 

Alternatively, high IL-21 levels in the skin (resulting from STAT3 activation by IL-6) stimulate skin cell multiplication and are associated with increased psoriasis severity [R, R]. In these cells, STAT3 activation by the cytokine IL-22 also increases skin inflammation and thickening [R, R].

Finally, STAT3 also induces the production of K17, a skin protein believed to trigger the autoimmune response in people with psoriasis, in response to cytokines such as IL-17, IL-22, and IFN-gamma [R, R, R]. This protein stabilized STAT3 in a cell-based study, possibly amplifying its own effects [R].

Taken together, STAT3 activation by IL-6 in T cells triggers and amplifies the inflammatory response associated with psoriasis. Its activation in skin cells worsens inflammation and causes skin thickening.

Increased STAT3 activity is a typical feature of psoriasis. In response to different cytokines, STAT3 contributes to the development and progression of psoriasis by promoting T-cell development and increasing skin inflammation and thickening.

The most widely-studied STAT3 polymorphism is rs744166. Although its mechanism remains unknown, some researchers have suggested that certain variants may alter the structure of the STAT3 protein and how it responds to cytokines. Because psoriasis seems associated with STAT3 activation, this variant may favor its interaction with cytokines such as IL-6, IL-21, IL-22, and IL-23 [R, R].

Two studies on over 7,500 European descendants and a Chinese population of almost 800 people associated the minor allele ‘G’ with an increased incidence of psoriasis [R, R]. However, the association didn’t reach statistical significance in another Chinese population [R]. The contribution of this allele to psoriasis may thus depend on the genetic composition of the different ethnic groups.

As previously mentioned, psoriasis may end up affecting the joints and developing into arthritis. In a Spanish population of over 2,000 people, the ‘GG’ genotype of rs744166 was associated with an increased frequency of psoriatic arthritis [R].

The ‘G’ allele of rs744166 has been associated with psoriasis in European descendants and one out of two Chinese populations evaluated. The ‘GG’ genotype was linked to psoriatic arthritis in a Spanish population.

Interactions with Other Genes

The binding of IL-23 to its receptor IL-23R can also activate the STAT3 protein and thus stimulate Th17 development and function. The ‘A’ variant of the rs11209026 polymorphism, which encodes a version of the IL-23R protein where an arginine is changed to glutamine, has been reported to protect against psoriasis and prevent STAT3 activation in response to IL-23 according to two studies in approximately 100 European participants [R, R].

You can see your genotype for the STAT3 rs744166 SNP in the table below. However, keep in mind that these results are based on association studies suggesting that certain genetic variants are more common in people with psoriasis. More research will be needed to know what role (if any) this variant plays in actually causing this condition. Also, many different factors, including other genetic and environmental factors, can influence the risk of psoriasis: therefore, just because you have one of these genotypes does not necessarily mean you are at increased risk of developing it!

Primary SNP: STAT3 rs744166:

• ‘A’ = Less common in people with psoriasis.
• ‘G’ = More common in people with psoriasis.

Population Frequency:

• Both homozygous genotypes are roughly similar in frequency. 44% of the world population has ‘AG’.
• In European descendants, the frequency of the ‘GG’ genotype is reduced to 19%.

Make sure to talk to your doctor if you think you may be experiencing symptoms of psoriasis, especially if you are concerned about the appearance of your skin or the condition causes you discomfort, makes performing routine tasks difficult, or affects the nails or joints. 

Although there is no cure for psoriasis, the symptoms can be managed with treatments that reduce inflammation and clear the skin. Mild to moderate cases are typically managed with topical creams, ointments, shampoos, and scalp solutions containing:

• Corticosteroids: they reduce inflammation and itching by targeting STAT3 and other pro-inflammatory pathways. However, they are not recommended in the long term because they may stop working over time and cause adverse effects such as skin thinning [R]
• Vitamin D analogs (such as calcipotriol): they slow skin cell growth, in part by reducing STAT3 expression [R].
• Anthralin: it helps reduce skin cell growth and remove scales but is messy and can irritate the skin.
• Vitamin A derivatives (retinoids): they may reduce inflammation but also increase sensitivity to sunlight. Interestingly, retinoids such as retinoic acid and acitretin reduced STAT3 activity in cell-based studies [R, R].
• Calcineurin inhibitors (such as tacrolimus and pimecrolimus): they reduce inflammation and plaque buildup but are not recommended in the long term because they may increase the risk of some cancer types.
• Salicylic acid: it reduces scaling and promotes the sloughing of dead skin. Although they were investigated for anticancer purposes in the study, salicylic acid derivatives reduced STAT3 activity in cells [R].
• Coal tar: it reduces itching, scaling, and inflammation, but stains clothing, has a strong smell, and may irritate the skin. Its component carbazole blocked STAT3 expression in cells. Because it makes the skin more receptive to UVB radiation, coal tar is used together with UVB phototherapy as part of the Goeckerman treatment [R].
• Moisturizers: they may reduce itching, scaling, and dryness.

Light therapy uses UV radiation and can be applied either alone or as an add-on to medications. The simplest way is to increase exposure to UV in sunlight or artificial light. Because intense UV exposure can damage the skin and worsen psoriasis symptoms, it’s important to consult a doctor about the safest ways to use it for psoriasis treatment.

Other forms of light therapy include:

• Broadband UVB phototherapy: controlled UVB doses may improve mild to moderate symptoms but may also cause adverse effects such as skin redness, itching, and dryness. In addition, UVB may increase inflammation and skin cell growth by activating STAT3. The direct targeting of more powerful UVB radiation to psoriasis plaques (excimer laser therapy) prevents adverse effects on healthy skin and requires fewer sessions [R, R].
• Narrow-band UVB: using a more narrow UVB wavelength range may be more effective to improve psoriasis symptoms, although it also increases the risk and severity of burns. As opposed to broadband UVB, this treatment reduced STAT3 activation and skin cell growth in cellular and animal studies [R, R].
• Goeckerman therapy: as previously described, this therapy combines coal tar with UVB phototherapy and is more effective than either treatment alone [R].
• Psoralen plus UVA (PUVA): this therapy combines the light-sensitizing medication psoralen with UVA radiation, which penetrates the skin deeper than UVB. The treatment is only used for severe cases because it’s more aggressive. As was the case for UVB, UVA may also increase skin cell growth through STAT3 activation [R, R].

When psoriasis is severe or resistant to other treatments, the symptoms can be managed with systemic (oral or injected) medications such as:

• Retinoids: oral retinoids such as acitretin may be more effective than topical preparations but may cause adverse effects such as lip inflammation and hair loss. Because they are associated with severe birth defects, women must avoid pregnancy for at least 3 years after taking this medication.
• Methotrexate: oral methotrexate reduces inflammation and skin cell production, but may cause digestive issues and fatigue in the short term, and liver damage and reduced blood cell production in the long term. Interestingly, this drug reduced STAT3 activation in cell-based studies [R, R].
• Cyclosporine: this immunosuppressant reduces inflammation but can only be taken short-term because it increases the risk of infections and cancer. As was the case for methotrexate, cyclosporine reduced STAT3 activation in cells [R].
• Biologic agents: these drugs are normally given by injection and interfere with the triggering of the immune system by suppressing specific components of inflammatory pathways. Two of them (etanercept and ustekinumab) were shown to reduce the expression of STAT3 (among other genes) in two studies on 33 psoriasis patients and matched healthy controls [R, R]. An oral JAK blocker approved for psoriatic arthritis (tofacitinib) reduced STAT3 activity in cells and is being investigated as a treatment for psoriasis [R, R, R, R].
• Other drugs, such as thioguanine and hydroxyurea, can be used in people not taking any other medications.