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TNF protein blocks inflammation, showing potential treatment for rheumatoid arthritis

Kathleen Blanchard's picture
Rheumatoid arthritis

Researchers have discovered a protein that could lead to new treatment for rheumatoid arthritis.

TNF (tumor necrosis factor) that is a pro-inflammatory cytokine is found by researchers at Hospital for Special Surgery in New York to also calm inflammation through a cascade of events that blocks the function of the A20 protein, implicated as a contributor to joint inflammation and destruction for rheumatoid arthritis.

The scientists explored TNF for treating rheumatoid arthritis based on evidence from past studies that it might calm, rather than promote inflammation.

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 explains, “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.”

Ivashkiv said the current study is the first to show TNF “can turn inflammation down”. The protein discovery means it could be used to control inflammation for rheumatoid arthritis in a way not previously understood.

In test tubes, the researchers studied human monocytes and macrophages that are cells that promote inflammatory diseases. The scientists treated the cells with TNF protein then noted what happens when they tried to induce inflammation.

Next they challenged the cells with lipopolysaccharide (LPS), a factor that stimulates inflammatory receptors, finding that TNF protected the cells from the inflammatory response that would normally be expected.

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TNF also protected mice from high doses of LPS that are considered lethal.

The researchers discovered GSK3 (glycogen synthase kinase 3-alpha) and a gene known as TNFAIP3 encode the protein A20. Blocking the effect of GSK3 and the gene boosts A20 that is produced in lower quantities in patients with inflammation, leading the scientists to suspect boosting the protein could provide a new treatment for rheumatoid arthritis.

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."

Two factors, GSK3 (glycogen synthase kinase 3-alpha) and a gene known as TNFAIP3 were found to be encoded the A20 gene. By blocking the action of the two with TNF inflammation was suppressed in test tube studies and in mice, indicating the treatment might also work for other inflammatory diseases and condition such as cancer when A20 suppression, rather than stimulation, is desirable.

The study identified a potential new treatment for rheumatoid arthritis using the protein TNF.

Nature Immunology (2011) doi:10.1038/ni.2043
"Tumor necrosis factor induces GSK3 kinase–mediated cross-tolerance to endotoxin in macrophages"
Sung Ho Park
Kyung-Hyun Park-Min
Janice Chen
Xiaoyu Hu
Lionel B Ivashkiv

Image: Wikimedia commons
Rheumatoid arthritis