Anti-Inflammatory Treatment Could Change as a Result of New Findings on Nuclear Receptor Proteins

Pharmaceutical Executive

Pharmaceutical Executive, Pharmaceutical Executive-09-13-2005, Volume 0, Issue 0

A University of California San Diego professor explains the results of his research on nuclear receptors and why these findings could lead to new therapies for autoimmune diseases.

What They Discovered:

Researchers at University of California San Diego revealed the mechanisms of three nuclear receptors involved in immune response. The receptors have differing but overlapping abilities to inhibit inflammation, offering opportunities to improve treatment of autoimmune diseases, according to the study published in the Sept. 9 issue of Cell.

    Inflammation is part of the immune response that normally results from bacterial or viral infection, lead author Christopher Glass said. The study focused on immune cells known as macrophages, which activate a number of genes in response to being exposed to a foreign agent. This response prepares the cell to kill an organism or recruit aid of other cells.

    But these immune responses are also central to chronic inflammatory diseases such as lupus, rheumatoid arthritis, and arteriosclerosis, Glass explained. The researchers wanted to identify how the process of inflammation could be controlled. They identified the three nuclear receptors in macrophage cells that were most potent in inhibiting inflammation.

    The glucocorticoid receptor is known to diminish inflammation and is the target of drugs for asthma, rheumatoid arthritis, and lupus. The PPAR gamma receptor is already the target of TZD drugs for type II diabetes. The third receptor is called LXR.

Potential Applications of the Results:

Because the receptors are involved with turning on and off different genes that have anti-inflammatory effects, they each regulate different parts of the immune response, Glass said. Compounds that promote activity for these receptors can be used in conjunction to create anti-inflammatory effects, he continued.

    As a result, drugs that activate these receptors could be used in conjunction, with smaller doses to diminish side effects. For example, glucocorticoids are known to have serious side effects such as high blood pressure, elevated glucose levels, thinning of skin, and bone loss, Glass said. He indicated that these side effects could be diminished if the patient took a low dose of glucocorticoids in combination with drugs that promote PPAR gamma or LXR receptors.

    Together, multiple drugs that activate nuclear receptors in the inflammation pathway could have a “synergistic effect” by maximizing anti-inflammatory results while minimizing side effects, Glass explained.

    “If you added the drugs together there would be a much stronger anti-inflammatory effect than by themselves,” Glass, a professor of cellular and molecular medicine, said.

    The authors compared this to “fine tuning” the body to balance immune responses with inflammatory responses that could lead to chronic autoimmune diseases.

    Glass said the results of this study could enable drug combinations to be tested in a clinical environment.

    He also indicated that these findings have implications for drug development. Knowing how these receptors interact with genes to elicit an anti-inflammatory response could be used to create new classes of drugs to act on these receptors more selectively.

    Understanding a mechanism that inhibits inflammation could allow researchers to develop tests to measure the specific activity of the receptor when exposed to different compounds, Glass said. This could be used as a screen for potential drugs, he continued.