Tumor Necrosis Factor Displays Anti-Inflammatory Behavior in Rheumatoid Arthritis

The proinflammatory protein tumor necrosis factor (TNF) has been found to have an additional, previously unsuspected anti-inflammatory function that might be coopted for treatment of chronic inflammatory conditions such as rheumatoid arthritis.

Investigators at the Hospital for Special Surgery (New York, NY, USA) worked with an in vitro model in which human monocytes and macrophages - cells that have a key role in inflammatory diseases - were treated with TNF and then challenged with LPS (lipopolysaccharide), a potent inflammatory factor that stimulates receptors important in inflammation.

They reported in the May 22, 2011, online edition of the journal Nature Immunology that TNF suppressed the inflammatory response of the macrophages and monocytes. Furthermore, in a set of in vivo experiments they found that mice treated with low doses of TNF were protected from subsequent lethal high doses of LPS. Suppression of the inflammatory response by TNF involved the protein GSK3 (glycogen synthase kinase 3-alpha) as well as the TNFAIP3 gene, which encodes the A20 protein.

"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," said senior author Dr. Lionel Ivashkiv, associate chief scientific officer at the Hospital for Special Surgery. "TNFAIP3 is one of the best linked genes to rheumatoid arthritis. There are polymorphisms in the A20 gene that have been linked to rheumatoid arthritis pathogenesis."

"Prior to this study, TNF has long been known as a potent proinflammatory 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," said Dr. Ivashkiv. "This is really the first mechanism showing how TNF can turn inflammation down."

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