News: Study of Nuclear Receptors Could Change Anti-inflammatory Treatments

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Source: University of California, San Diego Released: Thu 08-

Sep-2005, 08:45 ET

Embargo expired: Thu 08-Sep-2005, 12:00 ET

Study of Nuclear Receptors Could Change Anti-inflammatory Treatments

Newswise — 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, 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.”

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, Lozach, and

Pascual, UCSD Department of Cellular and Molecular Medicine;

Benner, UCSD Department of Cellular and Molecular Medicine and

Department of Bioengineering; Rajendra K. Tangirala and Stefan

Westin, X-Ceptor Therapeutics, San Diego; Hoffman, UCSD

Department of Chemistry and Biochemistry; Shankar Subramaniam, UCSD

Department of Bioengineering; , UCSD Department of

Biology; and G. Rosenfeld, UCSD Department of Medicine,

Medical Institute.