Interferon-Gamma Promotes UV-Induced Melanoma in Mice

After UV exposure, skin cells are damaged. Infiltrating macrophages move to the site and release interferon-gamma that binds to receptors on the sun-damaged melanocytes and enables them to evade detection by the immune system.

After UV exposure, skin cells are damaged. Infiltrating macrophages move to the site and release interferon-gamma that binds to receptors on the sun-damaged melanocytes and enables them to evade detection by the immune system. (Photo credit: Online Journal of Ophthalmology: www.onjoph.com)

Scientists have made an unanticipated discovery in mice that interferon-gamma, a type of protein primarily used by the immune system for intercellular communication, acts as a promoter for the deadly form of skin cancer known as melanoma. This finding resulted from a series of experiments designed to understand how solar ultraviolet (UV) radiation causes melanoma. This study suggests that interferon-gamma, which has been thought to contribute to an innate defense system against cancer, under some circumstances, may instead promote melanoma and incite the development of tumors.

Over the past 10 years, Glenn Merlino, Ph.D., working with his team in the Laboratory of Cancer Biology and Genetics and with his collaborators at George Washington University, used genetically engineered mice first to prove, and then to try to understand, the connection between exposure to UV radiation and the initiation of melanoma. The results published in this paper stem from the team’s latest attempt to define the molecular mechanisms of this cause and effect relationship.

Research fellow and first author M. Raza Zaidi, Ph.D., developed a genetically engineered mouse in which the melanocytes were exclusively labeled with a green fluorescent protein. This fluorescent tag allowed visual tracking and specific purification of melanocytes from the mouse skin. This enabled the researchers to evaluate the response of melanocytes to UV radiation exposure within the natural skin environment of a living animal.

The researchers observed that UV radiation doses equivalent to what would cause sunburn in human skin resulted the movement of increased numbers of melanocytes within the mouse skin. A detailed analysis of gene expression changes associated with this melanocyte movement revealed abnormal expression of a number of genes known to be responsive to interferon-gamma.

When interferon-gamma was inhibited at the time of UV radiation, the number of melanocytes and their movement remained normal, suggesting that interferon-gamma was responsible for the UV- radiation-induced activation of the melanocytes.

Immune cells called macrophages—cells that normally protect against infection—had infiltrated the mouse skin after UV exposure and were supplying interferon-gamma to the site. This effect was abolished when interferon-gamma was blocked, corroborating its importance in promoting melanoma development. Moreover, when the scientists examined human melanoma tissue samples, they found interferon-gamma-producing macrophages in 70 percent of the tumors, supporting the idea that these macrophages can significantly contribute to the initiation and/or progression of human melanoma.

The results of this study offer the possibility that the inhibition of interferon-gamma immediately after sunburn might block the carcinogenic activation of the skin’s pigment-producing cells, known as melanocytes, making it a potentially effective preventive strategy against UV radiation-induced melanoma. The work also points to the possibility of targeting the interferon-gamma pathway as a less toxic therapeutic alternative for the treatment of malignant melanoma patients.

Summary Posted: 02/2010

Reference

Zaidi MR, et al., <a href=" http://www.ncbi.nlm.nih.gov/pubmed/21248750" ">Interferon-gamma links ultraviolet radiation to melanomagenesis in mice</a>, Nature, Jan. 27, 2010, DOI: 10.1038/nature09666. PubMed Link