Gene for sex hormone synthesis could play key role in eczema
Potential new treatment target for common skin condition

Date:
September 20, 2021
Source:
UT Southwestern Medical Center
Summary:
A study led by dermatologists suggests that a common inflammatory
skin condition may stem from poorly regulated sex hormones. The
finding could offer an unexpected new target to fight this
condition.



FULL STORY ==========================================================================
A study led by UT Southwestern dermatologists suggests that a common inflammatory skin condition may stem from poorly regulated sex
hormones. The finding, published this week in PNAS, could offer an
unexpected new target to fight 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 U.S.

alone.

"We often think of eczema as a dry-skin condition and treat mild cases
with moisturizers," said corresponding author Tamia Harris-Tryon, M.D.,
Ph.D., Assistant Professor of Dermatology and Immunology at UTSW. "Here,
we're showing that a gene that's important for making sex hormones
seems to play a role in the skin making its own moisturizers. If we
could alter this gene's activity, we could potentially provide relief
to eczema patients by helping the skin make more oils and lipids to
moisturize itself." Dr. Harris-Tryon explained that previous research has linked AD to overactivity in 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 amount of the 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 was unknown.

To investigate this question, Dr. Harris-Tryon and her colleagues
focused on sebocytes, the cells that make up sebaceous glands. These
glands produce an oily, waxy barrier that coats the skin, helping 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 get a readout
on gene activity for the entire genome and compared it with gene activity
in sebocytes that weren't treated with these immune molecules. They found
that a gene called HSD3B1, which makes an enzyme called 3b-hydroxysteroid dehydrogenase 1, became up to 60 times more active when exposed to the
two interleukins.

The finding was a surprise, Dr. Harris-Tryon said, because this enzyme
is well known for playing a key role in the production of sex hormones
such as testosterone and progesterone, but it had never been linked to
atopic dermatitis and skin lipid production. Databases of human gene
activity showed that HSD3B1 tends to be overactive in patients with
eczema; a single study of patients on dupilumab showed that this drug
appears to lower HSD3B1's activity.

Both pieces of evidence suggest that IL-4 and IL-13 drive up the activity
of this gene.

To determine how this gene affects sebum output, the researchers
manipulated HSD3B1's activity in sebocytes growing in petri dishes. They
found that when they made this gene less active, the levels of sex
hormones decreased, and skin sebum production increased. The reverse
was also true, with more gene activity leading to higher amounts of sex hormones and less sebum. The researchers made similar findings in a mouse
model of AD, with sex hormone production decreasing the production of
skin lipids.

Together, Dr. Harris-Tryon said, these findings suggest that HSD3B1
could be a new target for fighting AD and potentially other forms of
eczema. "Changing the output of this gene could eventually offer a way
to treat AD that's completely different from any treatment that currently exists," she added.

Other UTSW researchers who contributed to this study include Chenlu
Zhang, Mahendran Chinnappan, Courtney A. Prestwood, Marshall Edwards,
Methinee Artami, Bonne M. Thompson, Kaitlyn M. Eckert, Goncalo Vale,
and Jeffrey G. McDonald.

Dr. Harris-Tryon is supported by the Robert Wood Johnson Foundation, the
UT Southwestern Disease-Oriented Clinical Scholars Program (DOCS), the Burroughs Wellcome Fund, and the National Institutes of Health (HL20948).

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Chenlu Zhang, Mahendran Chinnappan, Courtney A. Prestwood, Marshall
Edwards, Methinee Artami, Bonne M. Thompson, Kaitlyn M. Eckert,
Goncalo Vale, Christos C. Zouboulis, Jeffrey G. McDonald, Tamia
A. Harris-Tryon.

Interleukins 4 and 13 drive lipid abnormalities in skin cells
through regulation of sex steroid hormone synthesis. Proceedings of
the National Academy of Sciences, 2021; 118 (38): e2100749118 DOI:
10.1073/ pnas.2100749118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210920082147.htm

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