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| Several nuclear receptor proteins appear to overlap in their ability to exert
anti-inflammatory effects, according to new research by scientists at the
University of California, San Diego (UCSD). Nuclear receptors are important drug
targets for a number of diseases, for example, glucocorticoid receptors for
asthma and arthritis. But use of drugs targeting these receptors is sometimes
limited by unwelcome side effects. The new findings may suggest a way to
overcome this obstacle.
In a paper being published in the September 9 issue of the journal Cell,
Christopher Glass, M.D., Ph.D., professor of cellular and molecular medicine at
the UCSD School of Medicine, and his colleagues show that three nuclear receptor
proteins -- glucocorticoid, PPAR gamma and LXR -- can work together to repress
the cellular responses to certain kinds of pro-inflammatory molecular signaling.
These nuclear receptors are important in "turning off" inflammatory responses to
bacteria or viruses and allowing the cells to return to a normal state.
"Basically, we are looking at a 'tuning system' to maintain a proper level of
immunity, but without an inappropriate inflammatory response that would
contribute to a chronic disease state," Glass said.
The researchers have also, for the first time, identified on a genome-wide level
how these proteins work to influence the body's inflammatory response. By
identifying the molecular mechanism by which each receptor inhibits particular
genes involved in anti-viral responses, more powerful drugs could be developed
to fight immune diseases such as arteriosclerosis and arthritis, with fewer side
effects.
"We now have a molecular understanding of why inflammatory responses caused by
certain infections are sensitive to glucocorticoid drugs for example, while
others are resistant," said Glass. "These observations further explain how drugs
used to inhibit one type of inflammation could basically cripple the immune
system to respond to specific viral infections and make that disease much
worse."
Glass's studies of nuclear receptors have focused on their regulation of gene
expression in the macrophage, a basic cell that recognizes structures or
patterns on pathogens that aren't present in normal cells. The macrophage is
responsible for producing and responding to hormone-like molecules that control
inflammation -- important for the understanding of immune diseases such as
arteriosclerosis, psoriasis and rheumatoid arthritis that are triggered by
autoimmune responses. While macrophages and other immune cells are essential
against infectious organisms, they can also promote chronic inflammatory
diseases.
When the macrophage thinks it sees an infection, it "turns on" or expresses
hundreds of genes, enabling the macrophage to communicate with other cells and
combat infection. In some diseases, however, certain protein complexes become
modified and begin to look like the proteins associated with bacteria or
viruses. The macrophage misinterprets this pattern on a modified protein, which
causes it to initiate an inflammatory response. In this work, the UCSD team
looked at a number of pathogen-associated molecule patterns used to stimulate
the macrophage, with the long-term goal of finding a way to manage inflammation
without compromising the immune system.
While it had been shown in past studies that the macrophage responded to certain
drugs, it was never studied on a genomic-wide level how receptors actually did
the job of inhibiting the macrophage's inflammatory responses. The patterns
reported in the paper suggest that each of the receptors plays a slightly
different role in how the macrophage mounts an inflammatory response, working in
different but overlapping ways.
The findings also have potential clinical significance in showing how two or
three nuclear receptors activated at the same time very dramatically shut down
inflammatory responses. This suggests that the drug that works with one
particular receptor, but with negative side effects, could be given at a lower
dose along with different drugs targeting the other receptors. For example, one
class of potent corticoid drugs used to treat severe asthma has many negative
side effects, including high blood pressure, diabetes and obesity.
"What is of particular interest in this study," said Glass, "is that adding two
drugs together could have a much more substantial interaction while using much
less of each drug. This could result in much better therapeutic results with
fewer side effects. The observation that these proteins can function together
opens up new avenues of clinical investigation into the treatment of diseases."
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This work was supported by grants from the National Institutes of Health, the
Stanford Reynolds Center and the Sandler Program for Asthma Research.
Contributors to this paper include Sumito Ogawa, Jean Lozach, and Gabriel
Pascual, UCSD Department of Cellular and Molecular Medicine; Chris Benner, UCSD
Department of Cellular and Molecular Medicine and Department of Bioengineering;
Rajendra K. Tangirala and Stefan Westin, X-Ceptor Therapeutics, San Diego;
Alexander Hoffman, UCSD Department of Chemistry and Biochemistry; Shankar
Subramaniam, UCSD Department of Bioengineering; Michael David, UCSD Department
of Biology; and Michael G. Rosenfeld, UCSD Department of Medicine, Howard Hughes
Medical Institute.
The original news release can be found here.
http://ucsdnews.ucsd.edu/newsrel/health/09_08_Glass.asp
Alan
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