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Researchers discover key protein in psoriasis

13.12.2004


New find may be future target for medications to relieve common skin condition

Researchers at The University of Texas M. D. Anderson Cancer Center simultaneously have resolved a controversy over the cause of psoriasis and developed the first mouse model that fully mimics the human disorder. What’s more, the scientists have demonstrated they can block the signals that lead to psoriasis in their mouse model with a topical skin treatment that can prevent new outbreaks as well as treat existing psoriatic plaques. "We have developed a mouse model that exhibits all the major features of human psoriatic lesions and shown we can reverse those steps," said John DiGiovanni, Ph.D., the study’s principal investigator and director of M. D. Anderson’s Department of Carcinogenesis. "We may have found an entirely new treatment option for psoriasis."

The study, which appears in the January 2005 issue of the journal Nature Medicine, available on-line Dec. 12, shows a protein called STAT3 is a crucial initiator of psoriasis and must be present and activated for psoriasis to develop in their mouse model. Psoriasis is a chronic condition in which patches of skin become inflamed and develop itchy red, flaky scales. Areas of the body most affected include the scalp, elbows, knees, and lower back. Psoriasis affects about two percent of people worldwide, with men and women equally susceptible. Current treatment for psoriasis focuses on reducing inflammation and slowing down the rapid growth and shedding of skin cells called keratinocytes. There is no effective curative treatment for the underlying condition, according to DiGiovanni. "There has been an ongoing controversy about whether the primary defect in psoriasis is in the immune system or in the keratinocytes," says DiGiovanni. "We may have found the link - the change in keratinocytes that cooperates with the immune system cells necessary for development of human psoriasis."



The researchers became interested in STAT3 when they learned it was associated with wound healing, a process that shares many of the same molecular features with psoriasis and with cancer. DiGiovanni’s research team has recently shown that STAT3 is involved in the development of skin cancer and began investigating its role in psoriasis, another disease in which skin cells grow inappropriately.

STAT3 belong to a class of proteins called transcription factors, potent proteins that can set off a cascade of events by simultaneously activating many genes. In the case of STAT3, activation leads to the production of growth-promoting and cell survival proteins. Activated STAT3 is essential in normal skin to promote wound healing. When the healing process is complete, normal STAT3 returns to its inactive form. But when it fails to turn off, the wound healing process continues and skin cells proliferate.

The researchers first looked for activated STAT3 in the skin of psoriasis patients and found high levels of activated STAT3 in psoriasis lesions in 19 of 21 patients. Based on this observation, the researchers decided to develop a mouse model in which the gene that encodes STAT3 is always turned on in the keratinocyte skin cells. When the genetically altered mice were born they looked relatively normal, but by the time they were two weeks old, they began to develop scaly patches on their tails that sometimes spread to their lower back. When the scientists examined skin samples from the scaly patches they discovered that the patches mimicked human psoriasis very closely. "This mouse model recapitulated all of the major epidermal and immunological features of human psoriasis, something that other animal models fail to do," said DiGiovanni.

The researchers also noticed that if the animals suffered an abrasion, such as when they scratch themselves, they frequently developed a scaly lesion in the irritated area, just as many people develop psoriasis lesions after a mild injury - a characteristic called the Koebner phenomenon. DiGiovanni said this pattern is consistent with the idea that psoriasis is a form of over-active wound healing response.

In another experiment, the scientists transplanted skin from their STAT3 mice to a mouse that produces no T cells, a key component of the immune system that is believed to be necessary for development of psoriasis. The transplanted skin did not initially develop psoriasis lesions. However, when the scientists injected activated T cells into the skin grafts on T cell-free mice, the mice then developed psoriasis following mild injury. "This experiment showed it is necessary to have both activated STAT3 in keratinocytes and infiltrating, activated T cells to develop psoriasis," said DiGiovanni. "Neither is sufficient alone."

The scientists then tested whether blocking STAT3 could reverse the development of psoriasis. They applied a solution to the skin of their STAT3 mouse that contained a small piece of DNA called an oligonucleotide designed to bind STAT3 and prevent it from activating genes. The STAT3-blocking agent significantly halted the progress of the lesions and reversed symptoms such as slowing cell growth, shrinking dilated blood capillaries and reducing inflammation. "This study opens the door to a whole new kind of therapy for psoriasis," said DiGiovanni. "This is a brand new target for treatment."

He also noted that certain aspects of psoriasis and early stages of cancer development in skin share similarities. However, psoriasis never progresses to cancer, he noted. "We still have much to learn about psoriasis, and this mouse model will help us learn much more about the molecular events that happen during the disease process," he said. In addition, it may help us learn more about early stages of cancer and why certain changes favor one disease versus the other."

DiGiovanni’s collaborators included Shigetoshi Sano, M.D., Keith Syson Chan, Ph.D., Steve Carbajal, Mary Peavey, and Kaoru Kiguchi, M.D., Ph.D., of M. D. Anderson; John Clifford, Ph.D., Feist-Weiller Cancer Center and Louisiana State University, Shreveport, La.; Brian Nickoloff, M.D., Ph.D., Loyola University of Chicago; and Satoshi Itami, M.D., Ph.D., Osaka University Graduate School of Medicine, Osaka, Japan.

Julie A. Penne | EurekAlert!
Further information:
http://www.mdanderson.org

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