New Treatment for Rheumatoid Arthritis?
Reported May 25, 2011
(Ivanhoe Newswire) A powerful pro-inflammatory protein, tumor necrosis factor (TNF), can suppress aspects of inflammation. The identification of the mechanism of how this works could potentially lead to new treatment for rheumatoid arthritis.
“Prior to this study, TNF has long been known as a potent pro-inflammatory cytokine, but if you look carefully through the literature, there are hints that it also has some suppressive functions, but nothing was known about the mechanisms,” sid Lionel Ivashkiv, M.D., associate chief scientific officer and physician in the Arthritis and Tissue Degeneration Program at Hospital for Special Surgery who led the study, was quoted as saying. “This is really the first mechanism showing how TNF can turn inflammation down.”
Researchers designed experiments stimulating macrophages with lipopolysaccharide (LPS), a prototypical inflammatory factor that stimulates receptors important in inflammation. In test tube studies, the researchers treated human monocytes and macrophages, cells that have a key role in inflammatory diseases, with TNF and then challenged these cells with LPS.
They found that the TNF suppressed the inflammatory response of the macrophages and monocytes. They then gave mice low doses of TNF followed by high doses of LPS and found that the mice were protected from the effects of high dose LPS, which is usually lethal. They discovered that the mechanism by which TNF suppressed the inflammatory response involved a protein known as GSK3 (glycogen synthase kinase 3-alpha) and a gene known as TNFAIP3 that encodes the A20 protein. Experiments with a drug that can inhibit GSK3 as well as experiments with RNA interference of A20, which can block A20 gene function, helped identify the roles of this protein and gene.
“We think it is relevant to rheumatoid arthritis, not only because the cells we are studying (the macrophages) are exactly the same cells that migrate into joints and make the inflammatory cytokines involved in rheumatoid arthritis, but because A20 is involved. TNFAIP3 is one of the best linked genes to rheumatoid arthritis,” Dr. Ivashkiv said. “There are polymorphisms in the A20 gene that have been linked to RA pathogenesis.”
“What the study shows that is new is that TNF has suppressive functions in addition to its well-known activating functions,” Dr. Ivashkiv said. “Before this study, people thought it might suppress adaptive immunity, but surprisingly we found that it actually suppresses a cell of the innate immune system, the macrophage, which is the same cell that makes it and, by doing that, it regulates its own production.”
SOURCE: Nature Immunology, May 22, 2011