A study led by dermatologists at UT Southwestern suggests that a common inflammatory skin condition may stem from poorly regulated hormones. The finding could offer an unexpected new target to combat this condition.
Atopic dermatitis (AD) is a form of eczema. AD affects up to 13% of children and 10% of adults, with an annual treatment cost of $ 5.3 billion in the US alone.
“We often think of eczema as a dry skin condition and treat mild cases with moisturizers,” said corresponding author Tamia Harris-Tryon at UTSW. “Here, we are showing that a gene that is important for producing hormones appears to play a role in the skin in producing its own moisturizers.
“If we could alter the activity of this gene, we could provide relief for eczema patients by helping the skin produce more oils and lipids to hydrate.”
Dr. Harris-Tryon explained that previous research has linked AD to the overactivity of the genes responsible for the production of two inflammatory immune molecules, interleukins 4 and 13 (IL-4 and IL-13).
A relatively new drug called dupilumab, a monoclonal antibody that reduces the number of inflammatory molecules, has been extremely effective in many patients with moderate to severe AD. However, the molecular mechanisms behind how IL-4 and IL-13 contribute to this form of eczema were unknown.
To investigate this question, Dr. Harris-Tryon and her colleagues focused on sebocytes, the cells that make up the sebaceous glands. These glands produce an oily, waxy barrier that coats the skin and helps it retain moisture.
The researchers dosed human sebocytes growing in Petri dishes with IL-4 and IL-13, then used a technique called RNA sequencing to obtain a reading of the gene activity of the entire genome and compared it to the genetic activity in sebocytes that they were not treated with these immune molecules.
They discovered that a gene called HSD3B1, which produces an enzyme called 3b-hydroxysteroid dehydrogenase 1, became up to 60 times more active when exposed to the two interleukins.
The finding came as a surprise, Dr. Harris-Tryon said, because this enzyme is well known to play a key role in the production of hormones such as testosterone and progesterone, but has never been linked to atopic dermatitis and the production of skin lipids.
Databases of human genetic activity showed that HSD3B1 tends to be hyperactive in eczema patients; a single study of patients on dupilumab showed that this drug appears to decrease HSD3B1Activity of. Both tests suggest that IL-4 and IL-13 increase the activity of this gene.
To determine how this gene affects sebum production, the researchers manipulated HSD3B1Activity of sebocytes growing in Petri dishes. They found that when they made this gene less active, hormone levels decreased and the skin’s sebum production increased.
The reverse was also true, with increased genetic activity leading to higher amounts of hormones and less sebum. The researchers made similar findings in a mouse model of AD, with hormone production decreasing skin lipid production.
Together, said Dr. Harris-Tryon, these findings, published in TNAS, suggest that HSD3B1 it could be a new target to combat AD and potentially other forms of eczema.
“Changing the production of this gene could eventually offer a way to treat AD that is completely different from any treatment that currently exists,” he added. In fact, it is an exciting development.
Source: UT Southwestern Medical Center
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