D-Day for skin maladies?

April 1, 2007

Patient's skin treated with topical 1,25D3 showed increased protein expression of TLR2 and cathelicidin, with no evidence of inflammation.

The enzyme for processing 1,25D3 was known to be in skin cells but was thought to play a minor role in producing the hydroxylated form of the molecule.

That view has been dramatically upended with discoveries reported by Richard L. Gallo, M.D., Ph.D., in a paper that appeared in the Feb. 8 issue of the Journal of Clinical Investigation.

"We've been working on that problem for about five years and were surprised to find that the things that trigger inflammatory responses don't seem to have any effect," says the professor of medicine and chief of the division of dermatology at the University of California, San Diego School of Medicine, and head of the dermatology section of the Veterans Affairs San Diego Healthcare System.

Vitamin D discoveries

Drawing upon the work of others that showed vitamin D could regulate peptide expression in tissue culture cells, he wondered if the vitamin D metabolism system could be involved.

"Much to our surprise, we discovered that it is," Dr. Gallo says. "The way the skin responds to injury is by converting a precursor form of vitamin D to the active form of vitamin D. That sets off a cascade of immunological events that primes the innate immune system."

The enhanced metabolism of 1,25D3 induces expression of genes in keratinocytes that increase production of the antimicrobial peptide cathelicidin. Patient's skin treated with topical 1,25D3 showed increased protein expression of TLR2 and cathelicidin, with no evidence of inflammation.

The ratio of vitamin D to the precursor form is about 1000:1 in the skin.

"Following injury, enzymes turn on and convert it to the active form," Dr. Gallo explains. "That is the signal to keratinocytes and to other cells that it is time to increase the expression of the toll receptors and increase the release of these antimicrobial peptides."

Dr. Gallo believes, "The availability of 1,25D3 is essential to the wound." If that is true, it might help to explain why darker-skinned people, who process vitamin D less efficiently than fair-skinned people, are more susceptible to infections.

A broader role for D?

Dermatologists have long used topical vitamin D analogues in treating psoriasis.

The thought was that it probably affected the differentiation of keratinocytes.

Dr. Gallo is initiating a pilot study to treat "disorders that typically hadn't been thought of as vitamin D responses - things like acne, atopic dermatitis. Those are disorders where a more efficient immune system will improve the disease."

He is studying localized and systemic responses to both oral and topical administration of vitamin D supplementation. The oral dose being used is 3,000 units a day, well above normal dietary intake but half or less of the dose believed to be toxic.

"We already know that a topical application will increase the expression of TLR2 and the antimicrobials, but it is not clear what, if any, effect that might have on clinical disease," he says.

Dr. Gallo suspects that, eventually, his findings may have an impact on wound healing, as well as treatment of diabetic ulcers and rosacea, which may be caused by an overabundance of these peptides. Learning how to modulate the expression of these peptides may prove to be a useful part of therapy.