source: national psoriasis foundation march 2005
Researchers at the University of Texas M.D. Anderson Cancer Center in Houston, Texas 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. John DiGiovanni, Ph.D., director of M. D. Anderson’s Department of Carcinogenesis, was the study’s principal investigator. 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 cells, 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 mouse 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. “We’ve been waiting for such an animal model for a long time. This animal model indicates that you need both keratinocytes and T cells to create psoriasis lesions. If the model is validated from a pharmacological perspective, it will be a great tool for drug discovery,” says Brian Nickoloff, M.D., Ph.D., Loyola University of Chicago, who led an experiment within the study.
Multiple experiments lead to revelations
The researchers found that Stat3 is activated in the keratinocytes of human psoriasis lesions. Based on this finding, the researchers performed multiple experiments that led to their conclusion that the Stat3 protein is involved in psoriasis development. Mice expressing an active form of Stat3 (Stat3- active mice) developed psoriasis-like lesions that contained an increased number of inflammatory cells and other skin cells similar to those found in human psoriasis. Abrasions on the skin produced an increase in the amount of scale and other psoriasis symptoms, similar to those found in lesions that develop from the Koebner phenomenon in humans. In the Koebner phenomenon, areas of the skin that have been injured or traumatized sometimes develop psoriasis.
A topical treatment* designed to prevent Stat3 from activating Stat3 genes halted the development of the lesions and reversed skin symptoms in the Stat3-active mice.
Skin from Stat3-active mice was grafted onto nude mice (who lack T cells). The nude mice developed psoriasis-like lesions after injection of activated T cells, and showed an increase in the T cells involved in psoriasis. Both activated Stat3 in keratinocytes and T cells were required for the development of psoriasis-like lesions on the nude mice.
In a different grafting experiment, non-lesional skin from psoriasis patients was grafted onto SCID mice (who lack B and T cells). After injection of T cells the skin grafts showed substantial active Stat3. The researchers concluded that both Stat3 and T cells were required for psoriasis-like development.
Findings may bring new understanding of cause, treatment
It remains to be seen why Stat3 becomes activated in psoriatic skin. Many growth factors can lead to Stat-3 activation. 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.
In terms of psoriasis research, the mouse model may make it possible to define other elements involved in psoriasis development, thereby establishing the cause-and-effect types of relationships between the elements in the immune system and keratinocytes. “This is where a lot of research will be directed,” says Nickoloff.
*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 be completed, 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. |
