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Stat3 protein may be involved in psoriasis development

Researchers at the University of Texas M.D. Anderson Cancer Center in Houston collaborated with researchers in multiple locations to report in the January 2005 issue of Nature Medicine that a molecule called Stat3 may play a role in psoriasis development. The National Psoriasis Foundation hails the study as a promising step in understanding the complex development of psoriasis.

The study is unique in that it shows that Stat3 active keratinocytes (skin cells) and T cells are both needed for psoriasis development. Stat3 is a protein that is involved in a variety of biologic processes in the cell, including wound healing in the skin. Normally, Stat3 returns to its inactive form after the healing process is complete, but when it fails to turn off, the skin cells continue to multiply. Stat3 has been extensively studied, primarily in cancer research.

It also is the first study to have used a mouse model that recreated all of the features of human psoriasis; other animal models have not recreated all of the features, and many other studies on psoriasis genetics have used laboratory cultures that may fail to represent the biologic complexities of psoriasis development.

Multiple experiments lead to revelations
The researchers found activated Stat3 in the lesions of psoriasis patients, and also in the unaffected skin in some psoriatic patients. Based on this finding, the researchers performed multiple experiments that led to their conclusion that the Stat3 protein is involved in psoriasis development.

In the first experiment, the researchers used mice that have active Stat3 in their skin cells (Stat3-active mice). By two weeks, their skin became reddened and scaly, and psoriasis-like lesions developed in some of them. The researchers found an increased number of inflammatory cells and other skin cells that were similar to those found in human psoriasis.

The researchers also found that after wounding the skin, the areas around the wound showed an increase in the amount of scale and other psoriasis properties, similar to those found in lesions that develop in the Koebner phenomena in humans.

To follow the Koebner similarity, the researchers used tape stripping to chafe the skin by applying and pulling the tape off the skin. The researchers found a similar development of psoriasis-like lesions. In the Stat3-active mice, Stat3 was increased and several psoriasis-related genes were activated, including Vegfa, Tgfa, Icam1 and Nfkbia. The areas that had been tape-stripped showed increased blood vessels and psoriasis-like lesions.

The researchers analyzed the skin and found that Icam-1, an immune system molecule, was elevated in the keratinocyte skin cells of the Stat3-active mice. Icam-1 was further elevated by the tape stripping.

The researchers also used a solution that contained a small piece of DNA that was designed to prevent Stat3 from activating genes. The solution halted the development of the lesions and reversed skin symptoms in the Stat3-active mice.

The topical solution inhibited the elevation of Icam-1 expression, which led the researchers to suggest that T cells are recruited to the skin and activated by Icam-1 through LFA-1. In the Stat3-active mice, the skin that was altered by activated Stat-3 led to changes in the immune system.

In a different experiment, researchers grafted skin from the Stat3-active mice onto nude mice that lack T cells. The nude mice only developed psoriasis lesions after injection of activated T cells, and showed an increase in the T cells involved in psoriasis. The researchers found that both activated Stat3 in keratinocytes and T cells were required for the development of psoriasis on the nude mice. The control mice did not develop psoriatic lesions after injection with activated T cells together with tape stripping.

Researchers also performed a different grafting experiment in which they grafted non-lesional skin from psoriasis patients onto SCID mice (who lack B and T cells). After injection of T cells the skin grafts developed into psoriasis lesions on the SCID mice and showed substantial active Stat3. The researchers concluded that both Stat3 and T cells were required for psoriasis development.

Findings may bring new understanding of cause, treatment
However, it remains to be seen why Stat3 becomes activated in psoriatic skin. Many growth factors can lead to Stat-3 activation, including members of the IL-6, EGF, HGF families and others. The researchers speculate that growth factors produced during the wound healing process or secreted by activated T cells are likely to be responsible for activating Stat3 in psoriasis development.

The topical that inhibited psoriasis lesions is not available for treatment of psoriasis and was not studied in humans, but its use in the study may lead to development of a treatment. Typically, researchers study treatments in animal models before testing the treatment in humans. It can take years for the human studies of a new treatment to finish, and for the sponsor of the treatment to apply for approval from the U.S. Food and Drug Administration. The National Psoriasis Foundation supports the development of appropriate treatments for psoriasis and psoriatic arthritis.