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LOS ANGELES -- Researchers at UCLA have found that a member of the immune system's defense team stimulates a chain reaction leading to chronic anemia in many patients with infections and major inflammatory diseases. The study may help target new interventions to help prevent anemia in patients with rheumatoid arthritis and inflammatory bowel disease, which affect millions worldwide.
The new study, published in the May 1, 2004 issue of The Journal of Clinical Investigation, found that interleukin 6 - a protein that is part of the immune system is the signal that sets off a chain reaction during an infection or inflammatory state. Interleukin 6 stimulates an increase in the hormone Hepcidin, which in turn lowers the amount of iron in the bloodstream.
"We knew previously that the iron level in the blood drops during an infection or inflammatory state, but didn't know the molecular mechanism that sparks this response," said Tomas Ganz, PhD, MD, principal investigator and professor of medicine and pathology at the David Geffen School of Medicine at UCLA. "For the first time, we now can show the complete biological sequence of events leading to anemia in specific inflammatory diseases and infections."
Ganz adds that early during infection the body lowers the amount of iron in the bloodstream so infecting bacteria are starved for iron and can't grow. However, some inflammatory diseases ignite this reaction, even when no true infection is present, which can lead to chronic low iron, and inadequate iron supply for red blood cell production. Severe anemia caused by inflammatory diseases can lead to weakness and other symptoms, requiring blood transfusions or treatments that stimulate red cell production.
Infections and inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease are the second leading cause of anemia worldwide. Children with rheumatoid arthritis are especially susceptible to severe anemia.
During the study, researchers used three scenarios to prove the key role of interleukin 6 for the stimulation of Hepcidin and the lowering of blood iron: Investigators first added bacterial material to a culture of human liver cells and found that the production of Hepcidin increased. The increase could be blocked by adding anti-interleukin-6 antibodies that soaked up interleukin-6.
Researchers then generated an inflammatory response in special genetically-altered mice lacking interleukin 6 and found that there was no increase in Hepcidin and no drop in iron levels since no interleukin 6 was present. Lastly, researchers injected humans with interleukin 6, which stimulated an increase in the hormone Hepcidin leading to a lowering of iron in the bloodstream.
"Since we now better understand the early events leading to chronic anemia in specific inflammatory diseases, we may be able to block responses so patients can use more iron for red blood cell production," said Ganz.
According to Ganz, researchers also found that when humans or mice were given iron, the hormone Hepcidin increased, demonstrating that this hormone responds not only to inflammation but also to dietary iron. Earlier studies show that Hepcidin regulates how much iron is taken up from food and how it is distributed in the body.
Ganz notes that the next stage of research will involve looking at the role of Hepcidin in chronic inflammation leading to anemia, and continuing to study the molecular machinery of this important biological pathway.
The Will Rogers Fund funded the study.
Other study authors include: Elizabeth Nemeth, Seth Rivera, and Victoria Gabyan from the Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, Calif. and Charlotte Keller, Sarah Taudorf, and Bente K. Pedersen of The Copenhagen Muscle Research Centre and The Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.