Betulin and Its Derivatives Reduce Inflammation and COX-2 Activity in Macrophages

Betulin is a heavily studied natural compound for its use as an anticancer or pro-regenerative agent. The structural similarity between betulin to steroids gives rise to the idea that the substance may as well act as an anti-inflammatory drug. This study is the first to describe the anti-inflammatory properties of betulinic acid, betulin, and its derivatives with amino acids 1,4-diaminebutane (Dab), 1,3-diaminepropane (Dap), Ornithine (Orn), and lysine (Lys) on murine macrophages from lymphoma site. The compounds were compared to dexamethasone. To establish the response of the macrophages to the natural compounds, we tested the viability as well as sensitivity to the inflammatory signaling (IFN gamma R). IL-6 secretory properties and HSP-70 content in the cells were examined. Furthermore, we characterized the effects of compounds on the inhibition of cyclooxygenase-2 (COX-2) activity both in the enzymatic assays and molecular docking studies. Then, the changes in COX-2 expression after betulin treatment were assessed. Betulin and betulinic acid are the low-cytotoxicity compounds with the highest potential to decrease inflammation via reduced IL-6 secretion. To some extent, they induce the reorganization of IFN gamma R with nearly no effect on COX-2 activity. Conversely, Bet-Orn and Bet-Lys are highly cytotoxic and induce the aggregation of IFN gamma R. Besides, Bet-Lys reduces the activity of COX-2 to a higher degree than dexamethasone. Bet-Orn is the only one to increase the HSP-70 content in the macrophages. In case of IL-6 reduction, all compounds were more potent than dexamethasone.

Automated summary

Betulinic acid and betulin are compounds with anti-inflammatory properties and have the potential to reduce inflammation by reducing IL-6 secretion. They have minimal effect on COX-2 activity. Bet-Orn and Bet-Lys are highly cytotoxic and induce the aggregation of IFN gamma R. Bet-Lys has a higher degree of inhibition on COX-2 activity than dexamethasone. Bet-Orn is the only compound that increases the content of HSP-70 in macrophages. All compounds are more effective than dexamethasone in reducing IL-6.