Several nuclear receptor proteins appear to overlap in their ability toexert anti-inflammatory effects, according to new research byscientists at the University of California, San Diego (UCSD). Nuclearreceptors are important drug targets for a number of diseases, forexample, glucocorticoid receptors for asthma and arthritis. But use ofdrugs targeting these receptors is sometimes limited by unwelcome sideeffects. The new findings may suggest a way to overcome this obstacle.
In a paper being published in the September 9 issue of the journalCell, Christopher Glass, M.D., Ph.D., professor of cellular andmolecular medicine at the UCSD School of Medicine, and his colleaguesshow that three nuclear receptor proteins -- glucocorticoid, PPAR gammaand LXR -- can work together to repress the cellular responses tocertain kinds of pro-inflammatory molecular signaling. These nuclearreceptors are important in "turning off" inflammatory responses tobacteria or viruses and allowing the cells to return to a normal state.
"Basically, we are looking at a 'tuning system' to maintain aproper level of immunity, but without an inappropriate inflammatoryresponse that would contribute to a chronic disease state," Glass said.
The researchers have also, for the first time, identified on agenome-wide level how these proteins work to influence the body'sinflammatory response. By identifying the molecular mechanism by whicheach receptor inhibits particular genes involved in anti-viralresponses, more powerful drugs could be developed to fight immunediseases such as arteriosclerosis and arthritis, with fewer sideeffects.
"We now have a molecular understanding of why inflammatoryresponses caused by certain infections are sensitive to glucocorticoiddrugs for example, while others are resistant," said Glass. "Theseobservations further explain how drugs used to inhibit one type ofinflammation could basically cripple the immune system to respond tospecific viral infections and make that disease much worse."
Glass's studies of nuclear receptors have focused on theirregulation of gene expression in the macrophage, a basic cell thatrecognizes structures or patterns on pathogens that aren't present innormal cells. The macrophage is responsible for producing andresponding to hormone-like molecules that control inflammation --important for the understanding of immune diseases such asarteriosclerosis, psoriasis and rheumatoid arthritis that are triggeredby autoimmune responses. While macrophages and other immune cells areessential against infectious organisms, they can also promote chronicinflammatory diseases.
When the macrophage thinks it sees an infection, it "turns on"or expresses hundreds of genes, enabling the macrophage to communicatewith other cells and combat infection. In some diseases, however,certain protein complexes become modified and begin to look like theproteins associated with bacteria or viruses. The macrophagemisinterprets this pattern on a modified protein, which causes it toinitiate an inflammatory response. In this work, the UCSD team lookedat a number of pathogen-associated molecule patterns used to stimulatethe macrophage, with the long-term goal of finding a way to manageinflammation without compromising the immune system.
While it had been shown in past studies that the macrophageresponded to certain drugs, it was never studied on a genomic-widelevel how receptors actually did the job of inhibiting the macrophage'sinflammatory responses. The patterns reported in the paper suggest thateach of the receptors plays a slightly different role in how themacrophage mounts an inflammatory response, working in different butoverlapping ways.
The findings also have potential clinical significance inshowing how two or three nuclear receptors activated at the same timevery dramatically shut down inflammatory responses. This suggests thatthe drug that works with one particular receptor, but with negativeside effects, could be given at a lower dose along with different drugstargeting the other receptors. For example, one class of potentcorticoid drugs used to treat severe asthma has many negative sideeffects, including high blood pressure, diabetes and obesity.
"What is of particular interest in this study," said Glass, "isthat adding two drugs together could have a much more substantialinteraction while using much less of each drug. This could result inmuch better therapeutic results with fewer side effects. Theobservation that these proteins can function together opens up newavenues of clinical investigation into the treatment of diseases."
This work was supported by grants from the National Institutes ofHealth, the Stanford Reynolds Center and the Sandler Program for AsthmaResearch.
Contributors to this paper include Sumito Ogawa, Jean Lozach,and Gabriel Pascual, UCSD Department of Cellular and MolecularMedicine; Chris Benner, UCSD Department of Cellular and MolecularMedicine and Department of Bioengineering; Rajendra K. Tangirala andStefan Westin, X-Ceptor Therapeutics, San Diego; Alexander Hoffman,UCSD Department of Chemistry and Biochemistry; Shankar Subramaniam,UCSD Department of Bioengineering; Michael David, UCSD Department ofBiology; and Michael G. Rosenfeld, UCSD Department of Medicine, HowardHughes Medical Institute.
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