Pathway Offers Insight into Inflammation Regulation

Results were printed in the journal Immunity and illustrate that in patients suffering from RA the pathway fails to work properly as it would in healthy patients.

Immunity

Results were printed in the journal and illustrate that in individuals suffering from rheumatoid arthritis the pathway, known as DAP12-Syk-Pyk2-p38-MSK, fails to work properly.

"This is the first study to link this pathway to rheumatoid arthritis," said Lionel Ivashkiv, M.D., associate chief scientific officer at Hospital for Special Surgery in New York City and lead author, according to an article in the hospital’s website. "In the twenty years or so that I have been studying regulation of inflammation, this seems to be the most potent inhibitory mechanism that we have seen."

Dr. Ivashkiv’s past studies on inflammation have focused on identifying what regulates the production of cytokines, which are small proteins that regulate inflammation. Discovering the pathways involved in cytokine production can help researchers determine new methods of treating diseases that have malfunctioning cytokine proteins.

Going on past research that concludes immunorecptor tyrosine-based activation motif (ITAM)-coupled receptors were involved in regulating inflammation, the researchers began to devise a new study to determine how inflammatory signaling was actually turned off. This project was designed to investigate if an additional pathway may be triggered by the ITAM pathway, which would be responsible for inhibiting inflammation.

Reseachers “used fibrin(ogen) and immune complexes, proteins that are highly expressed at inflammatory sites, to activate the ITAM-associated receptors and then watched what happened.” The activation of the ITAM receptor set off the DAP12-Syk-Pyk2-p38-MSK pathway, which was “dependent on calcium signaling and discouraged pro-inflammatory cytokine.” ITAM receptors also induced an anti-inflammatory cytokine and certain protiens that have been associated with suppressing cytokines. It was also found that the ITAM inhibitory pathway does not function properly in those with inflammatory arthritis.

"When we looked at macrophages from patients with arthritis, we found that the whole inhibitory pathway would not work," Dr. Ivashkiv said. "What this study suggests is that one of the things that contribute to inflammation in arthritis is crippling of beneficial pathways that usually serve to turn inflammation off."

Researchers at the Hospital for Special Surgery studying inflammatory arthritis have identified a pathway involved in regulating the formation of inflammation.