Researchers Challenge Belief of How Macrophage Activity is Controlled by Biochemical ‘Brake Pedal’

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St. Jude researchers show that SOCS3 blocks only macrophage activation initiated by IL-6, and discover unexpected pathway by which macrophages can cause potentially fatal inflammatory responses

(MEMPHIS, TENN–May 29, 2003) A team of investigators at St. Jude Children's Research Hospital has challenged a currently held belief about how immune system cells called macrophages control their biochemical activity after being stimulated by signaling proteins called cytokines.

The researchers showed that a molecular "brake pedal" called SOCS3 slows the biochemical activity of macrophages only if they have been stimulated by a particular cytokine, IL-6. Macrophages are immune system cells in the blood that are the body's first line of defense against infections. SOCS3 is one of the SOCS (suppression of cytokine signaling) family of molecules that act as brake pedals on biochemical signaling pathways that turn specific cell functions on or off.

The finding adds to the understanding of how a critical signaling pathway called JAK/STAT operates in macrophages and other immune system cells. The study also unexpectedly discovered why a lack of the gene for SOCS3 can lead to a potentially serious runaway inflammatory response in humans.

The two discoveries made by the St. Jude team help to clarify an important part of the complex activities of the immune system, according to Peter Murray, PhD, Infectious Diseases. "The more we know about how cytokines control immune system cells like macrophages, and how the JAK/STAT system works, the closer we get to being able to exert fine control on the immune response when medically necessary," he said. Murray is senior author of an article on the research, which appears in the June issue of Nature Immunology.

Anne-Laure Pauleau made the discovery as part of the St. Jude team. Pauleau was a member of the "Paris Seven Program," which brings researchers from France to work in St. Jude laboratories. Roland Lang, the paper's first author, modified the immune systems of mice to produce animals that had both normal macrophages as well as macrophages that lacked the gene for SOCS3. This allowed Pauleau to study macrophages that had the SOCS3 gene and compare them to macrophages that lacked this gene. Lang is now at the Technical University in Munich, Germany.

Other authors of the study include Evan Parganas, Biochemistry; James N. Ihle, PhD, Biochemistry chair; Robert Rutschman, Infectious Diseases; Yutaka Takahashi (now at Kobe University Graduate School of Medicine in Kobe, Japan), and Jörg Mages (Technical University in Munich, Germany). This work was supported in part by grants from the U.S. National Institutes of Health and the American Heart Association, a grant from a National Cancer Center CORE grant. and ALSAC.

St. Jude Children's Research Hospital: St. Jude Children's Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital's work is supported through funds raised by ALSAC. ALSAC covers all costs not covered by insurance for medical treatment rendered at St. Jude Children's Research Hospital. Families without insurance are never asked to pay. For more information, please visit www.stjude.org.

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